Alkyl amides as hiv attachment inhibitors

ABSTRACT

Compounds of Formula (I), including pharmaceutically acceptable salts thereof, wherein A is selected from the group (II), are useful as HIV attachment inhibitors.

FIELD OF THE INVENTION

This invention provides compounds having drug and bio-affectingproperties, their pharmaceutical compositions and methods of use. Inparticular, the invention herein is directed to piperazine alkyl amidesas HIV attachment inhibitors that possess unique antiviral activity.

BACKGROUND OF THE INVENTION

HIV-1 (human immunodeficiency virus-1) infection remains a major medicalproblem, with an estimated 45 million people infected worldwide at theend of 2007. The number of cases of HIV and AIDS (acquiredimmunodeficiency syndrome) has risen rapidly. In 2005, approximately 5.0million new infections were reported, and 3.1 million people died fromAIDS. Currently available drugs for the treatment of HIV includenucleoside reverse transcriptase (RT) inhibitors or approved single pillcombinations: zidovudine (or AZT or RETROVIR®), didanosine (or VIDEX®),stavudine (or ZERIT®), lamivudine (or 3TC or EPIVIR®), zalcitabine (orDDC or HIVID®), abacavir succinate (or ZIAGEN®), tenofovir disoproxilfumarate salt (or VIREAD®), emtricitabine (or FTC—EMTRIVA®), COMBIVIR®(contains—3TC plus AZT), TRIZIVIR® (contains abacavir, lamivudine, andzidovudine), Epzicom (contains abacavir and lamivudine), TRUVADA®(contains VIREAD® and EMTRIVA®); non-nucleoside reverse transcriptaseinhibitors: nevirapine (or VIRAMUNE®), delavirdine (or RESCRIPTOR®) andefavirenz (or SUSTIVA®), Atripla (TRUVADA®+SUSTIVA®), and etravirine,and peptidomimetic protease inhibitors or approved formulations:saquinavir, indinavir, ritonavir, nelfinavir, amprenavir, lopinavir,KALETRA® (lopinavir and Ritonavir), darunavir, atazanavir (REYATAZ®) andtipranavir (APTIVUS®), and integrase inhibitors such as raltegravir(Isentress), and entry inhibitors such as enfuvirtide (T-20) (FUZEON®)and maraviroc (Selzentry).

Each of these drugs can only transiently restrain viral replication ifused alone. However, when used in combination, these drugs have aprofound effect on viremia and disease progression. In fact, significantreductions in death rates among AIDS patients have been recentlydocumented as a consequence of the widespread application of combinationtherapy. However, despite these impressive results, 30 to 50% ofpatients may ultimately fail combination drug therapies. Insufficientdrug potency, non-compliance, restricted tissue penetration anddrug-specific limitations within certain cell types (e.g., mostnucleoside analogs cannot be phosphorylated in resting cells) mayaccount for the incomplete suppression of sensitive viruses.Furthermore, the high replication rate and rapid turnover of HIV-1combined with the frequent incorporation of mutations, leads to theappearance of drug-resistant variants and treatment failures whensub-optimal drug concentrations are present. Therefore, novel anti-HIVagents exhibiting distinct resistance patterns, and favorablepharmacokinetic as well as safety profiles are needed to provide moretreatment options. Improved HIV fusion inhibitors and HIV entrycoreceptor antagonists are two examples of new classes of anti-HIVagents further being studied by a number of investigators.

HIV attachment inhibitors are a novel subclass of antiviral compoundsthat bind to the HIV surface glycoprotein gp120, and interfere with theinteraction between the surface protein gp120 and the host cell receptorCD4. Thus, they prevent HIV from attaching to the human CD4 T-cell, andblock HIV replication in the first stage of the HIV life cycle. Theproperties of HIV attachment inhibitors have been improved in an effortto obtain compounds with maximized utility and efficacy as antiviralagents. A disclosure describing indoles of which the structure shownbelow for BMS-705 is representative, has been disclosed (AntiviralIndoleoxoacetyl piperazine Derivatives).

Two other compounds, referred to in the literature as BMS-806 andBMS-043 have been described in both the academic and patent art:

Some description of their properties in human clinical trials has beendisclosed in the literature.

It should be noted that in all three of these structures, a piperazineamide (in these three structures a piperazine phenyl amide) is presentand this group is directly attached to an oxoacetyl moiety. Theoxoacetyl group is attached at the 3-position of 4-fluoro indole inBMS-705 and to the 3 position of substituted azaindoles in BMS-806 andBMS-043.

In an effort to obtain improved anti-HIV compounds, later publicationsdescribed in part, modified substitution patterns on the indoles andazaindoles. Examples of such efforts include: (1) novel substitutedindoleoxoacetic piperazine derivatives, (2) substitutedpiperazinyloxoacetylindole derivatives, and (3) substitutedazaindoleoxoacetic piperazine derivatives.

Replacement of these groups with other heteroaromatics or substitutedheteroaromatics or bicyclic hydrocarbons was also shown to be feasible.Examples include: (1) indole, azaindole and related heterocyclicamidopiperazine derivatives; (2) bicyclo 4.4.0 antiviral derivatives;and (3) diazaindole derivatives.

A select few replacements for the piperazine amide portion of themolecules have also been described in the art and among these examplesare (1) some piperidine alkenes; (2) some pyrrolidine amides; (3) someN-aryl or heteroaryl piperazines; (4) some piperazinyl ureas; and (5)some carboline-containing compounds.

Method(s) for preparing prodrugs for this class of compounds aredisclosed in Prodrugs of piperazine and Substituted Piperidine AntiviralAgents (Ueda et al., U.S. non-provisional application Serial. No.11/066,745, filed Feb. 25, 2005 or U.S. Publication No. 2005/0209246 orWO 2005/090367 A1).

A published PCT patent application WO 2003/103607 A1 (Jun. 11, 2003)disclosures an assay useful for assaying some HIV inhibitors.

Several published patent applications describe combination studies withpiperazine benzamide inhibitors, for example, U.S. Publication No.2005/0215543 (WO 2005/102328 A1), U.S. Publication No. 2005/0215544 (WO2005/102391 A1), and U.S. Publication No. 2005/0215545 (WO 2005/102392A2).

A publication on new compounds in this class of attachment inhibitors(Wang, J. et al., Org. Biol. Chem., 3:1781-1786 (2005)) and a patentapplication on some more remotely related compounds have appeared WO2005/016344 published on Feb. 24, 2005.

Published patent applications WO 2005/016344 and WO 2005/121094 alsodescribe piperazine derivatives which are HIV inhibitors. Otherreferences in the HIV attachment area include U.S. Publication Nos.2007/0155702, 2007/0078141 and 2007/0287712, WO 2007/103456, as well asU.S. Pat. Nos. 7,348,337 and 7,354,924. A literature reference is J.Med. Chem., 50:6535 (2007).

What is therefore needed in the art are new HIV attachment inhibitorcompounds, and compositions thereof, which are efficacious against HIVinfection.

Of particular interest are new piperazine alkyl amides as HIV attachmentinhibitor compounds, described herein. The compounds of the presentinvention are alkyl amide derivatives, which are structurally distinctfrom the aryl amide HIV attachment inhibitors set forth in literature.

SUMMARY OF THE INVENTION

The present invention provides compounds of Formula I below, thepharmaceutically acceptable salts and/or solvates (e.g., hydrates)thereof, their pharmaceutical formulations, and their use in patientssuffering from or susceptible to a virus such as HIV. The compounds ofFormula I, their pharmaceutically acceptable salts and/or solvates areeffective antiviral agents, particularly as inhibitors of HIV. They areuseful for the treatment of HIV and AIDS.

One embodiment of the present invention is directed to a compound ofFormula I, including pharmaceutically acceptable salts thereof:

wherein A is selected from the group consisting of:

whereina, b, c, d and e are independently selected from the group consisting ofhydrogen, halogen, cyano, nitro, COOR⁵⁶, XR⁵⁷, NA¹A², C(O)R⁷,C(O)NR⁵⁵R⁵⁶, B, Q, and E;B is selected from the group consisting of —C(═NR⁴⁶)(R⁴⁷), C(O)NR⁴⁰R⁴¹,aryl, heteroaryl, heteroalicyclic, S(O)₂R⁸, C(O)R⁷, XR^(8a),(C₁₋₆)alkylNR⁴⁰R⁴¹, (C₁₋₆)alkylCOOR^(8b); wherein said aryl, heteroaryl,and heteroalicyclic are optionally substituted with one to three same ordifferent halogens or from one to three same or different substituentsselected from the group F; wherein aryl is napthyl or substitutedphenyl; wherein heteroaryl is a mono or bicyclic system which containsfrom 3 to 7 ring atoms for a mono cyclic system and up to 12 atoms in afused bicyclic system, including from 1 to 4 heteroatoms; whereinheteroalicyclic is a 3 to 7 membered mono cyclic ring which may containfrom 1 to 2 heteroatoms in the ring skeleton and which may be fused to abenzene or pyridine ring;Q is selected from the group consisting of (C₁₋₆)alkyl and(C₂₋₆)alkenyl; wherein said (C₁₋₆)alkyl and (C₂₋₆)alkenyl are optionallysubstituted with one to three same or different halogens or from one tothree same or different substituents selected from the group consistingof C(O)NR⁵⁵R⁵⁶, hydroxy, cyano and XR⁵⁷;E is selected from the group consisting of (C₁₋₆)alkyl and(C₂₋₆)alkenyl; wherein said (C₁₋₆)alkyl and (C₂₋₆)alkenyl areindependently optionally substituted with a member selected from thegroup consisting of phenyl, heteroaryl, SMe, SPh,—C(O)NR⁵⁶R⁵⁷, C(O)R⁵⁷, SO₂(C₁₋₆)alkyl and SO₂Ph; wherein heteroaryl is amonocyclic system which contains from 3 to 7 ring atoms, including from1 to 4 heteroatoms;R⁷ is selected from the group consisting of aryl, heteroaryl, andheteroalicyclic; wherein said aryl, heteroaryl, and heteroalicyclic areoptionally substituted with one to three same or different halogens orwith from one to three same or different substituents selected from thegroup F;wherein for R⁷, R⁸, R^(8a), R^(8b) aryl is phenyl; heteroaryl is a monoor bicyclic system which contains from 3 to 7 ring atoms for mono cyclicsystems and up to 10 atoms in a bicyclic system, including from 1 to 4heteroatoms; wherein heteroalicyclic is selected from the groupconsisting of aziridine, azetidine, pyrrolidine, piperazine, piperidine,tetrahydrofuran, tetrahydropyran, azepine, and morpholine;F is selected from the group consisting of (C₁₋₆)alkyl,(C₃₋₇)cycloalkyl, aryl, heteroaryl, heteroalicyclic, hydroxy,(C₁₋₆)alkoxy, aryloxy, (C₁₋₆)thioalkoxy, cyano, halogen, nitro,—C(O)R⁵⁷, benzyl, —NR⁴²C(O)—(C₁₋₆)alkyl, —NR⁴²C(O)—(C₃₋₆)cycloalkyl, —NR⁴²C(O)-aryl, —NR⁴²C(O)-heteroaryl,—NR⁴²C(O)-heteroalicyclic, a 4, 5, or 6 membered ring cyclic N-lactam,—NR⁴²S(O)₂—(C₁₋₆)alkyl, —NR⁴²S(O)₂—(C₃₋₆)cycloalkyl, —NR⁴²S(O)2-aryl,—NR⁴²S(O)₂-heteroaryl, —NR⁴²S(O)2-heteroalicyclic, S(O)₂(C₁₋₆)alkyl,S(O)₂aryl, —S(O)2 NR⁴²R⁴³, NR⁴²R⁴³,(C₁₋₆)alkylC(O)NR⁴²R⁴³, C(O)NR⁴²R⁴³, NHC(O)NR⁴²R⁴³, OC(O)NR⁴²R⁴³,NHC(O)OR⁵⁴, (C₁₋₆)alkylNR⁴²R⁴³, COOR⁵⁴, and (C₁₋₆)alkylCOOR⁵⁴; whereinsaid (C₁₋₆)alkyl, (C₃₋₇)cycloalkyl, aryl, heteroaryl, heteroalicyclic,(C₁₋₆)alkoxy, and aryloxy, are optionally substituted with one to ninesame or different halogens or from one to five same or differentsubstituents selected from the group G; wherein aryl is phenyl;heteroaryl is a monocyclic system which contains from 3 to 7 ring atoms,including from 1 to 4 heteroatoms; heteroalicyclic is selected from thegroup consisting of aziridine, azetidine, pyrrolidine, piperazine,piperidine, tetrahydrofuran, tetrahydropyran, azepine, and morpholine;R⁸ is selected from the group consisting of hydrogen, (C₁₋₆)alkyl,(C₃₋₇)cycloalkyl, (C₂₋₆)alkenyl, (C₃₋₇)cycloalkenyl, (C₂₋₆)alkynyl,aryl, heteroaryl, and heteroalicyclic; wherein said (C₁₋₆)alkyl,(C₃₋₇)cycloalkyl, (C₂₋₆)alkenyl, (C₃₋₇)cycloalkenyl, (C₂₋₆)alkynyl,aryl, heteroaryl, and heteroalicyclic are optionally substituted withone to six same or different halogens or from one to five same ordifferent substituents selected from the group F or (C₁₋₆)alkyl,(C₃₋₆)cycloalkyl, cyano, phenyl, aryl, heteroaryl, heteroalicyclic,hydroxy, (C₁₋₆)alkoxy, halogen, benzyl, primary amine, secondary amine,tertiary amine, ammonium, nitro, thiol, thioether, alcohol, ether, acid,aldehyde, ketone, amide, amidine, guanidine, sulfone, sulfonamide,sulfamide, acyl sulfamide, sulfate, sulfuric acid, sulfamic acid,phosphate, phosphoric acid, boronic ester, boronic acid, squarate,squaric acid, oxime, hydrazine, peroxide, among which ether, peroxide,thioether, secondary amine, tertiary amine, ammonium, ester, ketone,amide, amidine, oxime, hydrazine can be either acyclic or cyclic;heteroaryl is selected from the group consisting of furanyl, thienyl,thiazolyl, isothiazolyl, oxazolyl, isoxazolyl, imidazolyl, oxadiazolyl,thiadiazolyl, pyrazolyl, tetrazolyl, triazolyl, pyridinyl, pyrazinyl,pyridazinyl, and pyrimidinyl;R^(8a) is a member selected from the group consisting of aryl,heteroaryl, and heteroalicyclic; wherein each member is independentlyoptionally substituted with one to six same or different halogens orfrom one to five same or different substituents selected from the groupF;R^(8b) is selected from the group consisting of hydrogen, (C₁₋₆)alkyland phenyl;X is selected from the group consisting of NH or NCH₃, O, and S;R⁴⁰ and R⁴¹ are independently selected from the group consisting of(a) hydrogen; (b) (C₁₋₆)alkyl or (C₃₋₇)cycloalkyl substituted with oneto three same or different halogens or from one to two same or differentsubstituents selected from the group F or different functional groups:(C₁₋₆)alkyl, (C₃₋₆)cycloalkyl, cyano, phenyl, aryl, heteroaryl,heteroalicyclic, hydroxy, (C₁₋₆)alkoxy, halogen, benzyl, primary amine,secondary amine, tertiary amine, ammonium, nitro, thiol, thioether,alcohol, ether, acid, aldehyde, ketone, amide, amidine, guanidine,sulfone, sulfonamide, sulfamide, acyl sulfamide, sulfate, sulfuric acid,sulfamic acid, phosphate, phosphoric acid, boronic ester, boronic acid,squarate, squaric acid, oxime, hydrazine, peroxide, among which ether,peroxide, thioether, secondary amine, tertiary amine, ammonium, ester,ketone, amide, amidine, oxime, hydrazine can be either acyclic orcyclic; heteroaryl is selected from the group consisting of furanyl,thienyl, thiazolyl, isothiazolyl, oxazolyl, isoxazolyl, imidazolyl,oxadiazolyl, thiadiazolyl, pyrazolyl, tetrazolyl, triazolyl, pyridinyl,pyrazinyl, pyridazinyl, and pyrimidinyl; and (c) (C₁₋₆)alkoxy, aryl,heteroaryl or heteroalicyclic; or R⁴⁰ and R⁴¹ taken together with thenitrogen to which they are attached form a member selected from thegroup consisting of aziridine, azetidine, pyrrolidine, piperazine, 4—NMepiperazine, piperidine, azepine, and morpholine; and wherein said aryl,heteroaryl, and heteroalicyclic are optionally substituted with one tothree same or different halogens or from one to two same or differentsubstituents selected from the group F; wherein for R⁴⁰ and R⁴¹ aryl isphenyl; heteroaryl is a monocyclic system which contains from 3 to 6ring atoms, including from 1 to 4 heteroatoms; heteroalicyclic isselected from the group consisting of aziridine, azetidine, pyrrolidine,piperazine, piperidine, tetrahydrofuran, tetrahydropyran, azepine, andmorpholine; provided when B is C(O)NR⁴⁰R⁴¹, at least one of R⁴⁰ and R⁴¹is not selected from groups (a) or (b);R⁴² and R⁴³ are independently selected from the group consisting ofhydrogen, (C₁₋₆)alkyl, allyl, (C₁₋₆)alkoxy, (C₃₋₇)cycloalkyl, aryl,heteroaryl and heteroalicyclic; or R⁴² and R⁴³ taken together with thenitrogen to which they are attached form a member selected from thegroup consisting of aziridine, azetidine, pyrrolidine, piperazine, 4—NMepiperazine, piperidine, azepine, and morpholine; and wherein said(C₁₋₆)alkyl, (C₁₋₆)alkoxy, (C₃₋₇)cycloalkyl, aryl, heteroaryl, andheteroalicyclic are optionally substituted with one to three same ordifferent halogens or from one to two same or different substituentsselected from the group G or different functional groups: (C₁₋₆)alkyl,(C₃₋₆)cycloalkyl, cyano, phenyl, aryl, heteroaryl, heteroalicyclic,hydroxy, (C₁₋₆)alkoxy, halogen, benzyl, primary amine, secondary amine,tertiary amine, ammonium, nitro, thiol, thioether, alcohol, ether, acid,aldehyde, ketone, amide, amidine, guanidine, sulfone, sulfonamide,sulfamide, acyl sulfamide, sulfate, sulfuric acid, sulfamic acid,phosphate, phosphoric acid, boronic ester, boronic acid, squarate,squaric acid, oxime, hydrazine, peroxide, among which ether, peroxide,thioether, secondary amine, tertiary amine, ammonium, ester, ketone,amide, amidine, oxime, hydrazine can be either acyclic or cyclic;heteroaryl is selected from the group consisting of furanyl, thienyl,thiazolyl, isothiazolyl, oxazolyl, isoxazolyl, imidazolyl, oxadiazolyl,thiadiazolyl, pyrazolyl, tetrazolyl, triazolyl, pyridinyl, pyrazinyl,pyridazinyl, and pyrimidinyl; wherein for R⁴² and R⁴³ aryl is phenyl;heteroaryl is a monocyclic system which contains from 3 to 6 ring atoms,including from 1 to 4 heteroatoms; heteroalicyclic is a member selectedfrom the group consisting of aziridine, azetidine, pyrrolidine,piperazine, piperidine, tetrahydrofuran, tetrahydropyran, azepine, andmorpholine;G is selected from the group consisting of (C₁₋₆)alkyl,(C₃₋₇)cycloalkyl, aryl, heteroaryl, heteroalicyclic, hydroxy,(C₁₋₆)alkoxy, aryloxy, cyano, halogen, nitro, —C(O)R⁵⁷, benzyl,—NR⁴⁸C(O)—(C₁₋₆)alkyl, —NR⁴⁸C(O)—(C₃₋₆)cycloalkyl, —NR⁴⁸C(O)-aryl,—NR⁴⁸C(O)-heteroaryl, —NR⁴⁸C(O)-heteroalicyclic, a 4, 5, or 6 memberedring cyclic N-lactam, —NR⁴⁸S(O)₂—(C₁₋₆)alkyl, —NR⁴⁸S(O)₂—(C₃₋₆)cycloalkyl, —NR⁴⁸S(O)2-aryl, —NR⁴⁸S(O)₂-heteroaryl,—NR⁴⁸S(O)2-heteroalicyclic, sulfinyl, sulfonyl, sulfonamide, NR⁴⁸R⁴⁹,(C₁₋₆)alkyl C(O)NR⁴⁸R⁴⁹, C(O)NR⁴⁸R⁴⁹, NHC(O)NR⁴⁸R⁴⁹, OC(O)NR⁴⁸R⁴⁹,NHC(O)OR^(54′),(C₁₋₆)alkylNR⁴⁸R⁴⁹, COOR⁵⁴, and (C₁₋₆)alkylCOOR⁵⁴; whereinaryl is phenyl; heteroaryl is a monocyclic system which contains from 3to 7 ring atoms, including from 1 to 4 heteroatoms; heteroalicyclic isselected from the group consisting of aziridine, azetidine, pyrrolidine,piperazine, piperidine, tetrahydrofuran, tetrahydropyran, azepine, andmorpholine;R⁴⁶ is selected from the group consisting of H, OR⁵⁷, and NR⁵⁵R⁵⁶;R⁴⁷ is selected from the group consisting of H, amino, halogen, phenyl,aryl, heteroaryl and (C₁₋₆)alkyl;R⁴⁸ and R⁴⁹ are independently selected from the group consisting ofhydrogen, (C₁₋₆)alkyl, phenyl, aryl and heteroaryl;R⁵⁰ is selected from the group consisting of H, (C₁₋₆)alkyl,(C₃₋₆)cycloalkyl, and benzyl; wherein each of said (C₁₋₆)alkyl,(C₃₋₇)cycloalkyl and benzyl are optionally substituted with one to threesame or different (C₁₋₆)alkyl, (C₃₋₆)cycloalkyl, cyano, phenyl, aryl,heteroaryl, heteroalicyclic, hydroxy, (C₁₋₆)alkoxy, halogen, benzyl,primary amine, secondary amine, tertiary amine, ammonium, nitro, thiol,thioether, alcohol, ether, acid, aldehyde, ketone, amide, amidine,guanidine, sulfone, sulfonamide, sulfamide, acyl sulfamide, sulfate,sulfuric acid, sulfamic acid, phosphate, phosphoric acid, boronic ester,boronic acid, squarate, squaric acid, oxime, hydrazine, peroxide, amongwhich ether, peroxide, thioether, secondary amine, tertiary amine,ammonium, ester, ketone, amide, amidine, oxime, hydrazine can be eitheracyclic or cyclic; heteroaryl is selected from the group consisting offuranyl, thienyl, thiazolyl, isothiazolyl, oxazolyl, isoxazolyl,imidazolyl, oxadiazolyl, thiadiazolyl, pyrazolyl, tetrazolyl, triazolyl,pyridinyl, pyrazinyl, pyridazinyl, and pyrimidinylR⁵⁴ is selected from the group consisting of hydrogen and (C₁₋₆)alkyl;R^(54′) is (C₁₋₆)alkyl;R⁵⁵ and R⁵⁶ are independently selected from the group consisting ofhydrogen and (C₁₋₆)alkyl; andR⁵⁷ is selected from the group consisting of hydrogen, (C₁₋₆)alkyl,aryl, heteroaryl; andA¹ and A² are independently selected from hydrogen, (C₁₋₆)alkyl, aryl,heteroaryl, SO2D¹, SO2ND²D³, COD⁴, COCOD⁴, COOD⁴, COND⁵D⁶, COCOND⁵D⁶,COCOOD⁴, C(═ND⁷)D⁸, C(═ND⁹)ND¹⁰D¹¹;A¹ and A² can either never connect with each other, or conjoin to form aring structure;D¹, D², D³, D⁴, D⁵, D⁶, D⁷, D⁸, D⁹, D¹⁰, and D¹¹ are each independentlyselected from the group consisting of H, C₁-C₅₀ alkyl, C₃-C₅₀cycloalkyl, C₃-C₅₀ alkenyl, C₄-C₅₀ cycloalkenyl, phenyl, heteroaryl,C₃-C₅₀ amide and C₃-C₅₀ ether; heteroaryl is selected from the groupconsisting of pyridinyl, pyrazinyl, pyridazinyl, pyrimidinyl, furanyl,thienyl, benzothienyl, thiazolyl, isothiazolyl, oxazolyl, benzooxazolyl,isoxazolyl, imidazolyl, benzoimidazolyl, 1H-imidazo[4,5-b]pyridin-2-yl,1H-imidazo[4,5-c]pyridin-2-yl, oxadiazolyl, thiadiazolyl, pyrazolyl,tetrazolyl, tetrazinyl, triazinyl and triazolyl; provided the carbonatoms which comprise the carbon-carbon double bond of said C₃-C₂₀alkenyl or the carbon-carbon triple bond of said C₃-C₂₀ alkynyl are notthe point of attachment to the nitrogen to which D², D³, D⁵, D⁶, D⁷, D⁹,D¹⁰, and D¹¹ is attached; wherein said C₁-C₅₀ alkyl, C₃-C₅₀ cycloalkyl,C₃-C₅₀ alkenyl, C₄-C₅₀ cycloalkenyl, aryl, phenyl, heteroaryl, C₃-C₅₀amide and C₃-C₅₀ ether is optionally substituted with one to three sameor different of the following functionalities: (C₁₋₆)alkyl,(C₃₋₆)cycloalkyl, cyano, phenyl, aryl, heteroaryl, heteroalicyclic,hydroxy, (C₁₋₆)alkoxy, halogen, benzyl, primary amine, secondary amine,tertiary amine, ammonium, nitro, thiol, thioether, alcohol, ether, acid,aldehyde, ketone, amide, amidine, guanidine, sulfone, sulfonamide,sulfamide, acyl sulfamide, sulfate, sulfuric acid, sulfamic acid,phosphate, phosphoric acid, boronic ester, boronic acid, squarate,squaric acid, oxime, hydrazine, peroxide, among which ether, peroxide,thioether, secondary amine, tertiary amine, ammonium, ester, ketone,amide, amidine, oxime, hydrazine can be either acyclic or cyclic;I₁, I₂, I₃, I₄, I₅, I₆, I₇ and I₈ are each independently selected fromthe group consisting of H, (C₁₋₆)alkyl, (C₃₋₆) cycloalkyl, (C₂₋₆)alkenyl, (C₄₋₆) cycloalkenyl, (C₂₋₆) alkynyl, CR₈₁R₈₂OR₈₃, COR₈₄,COOR₈₅, or CONR₈₆R₈₇; wherein each of said alkyl and cycloalkyl beingoptionally substituted with one to three same or different cyano,phenyl, aryl, heteroaryl, heteroalicyclic, hydroxy, (C₁₋₆)alkoxy,halogen, benzyl, primary amine, secondary amine, tertiary amine,ammonium, nitro, thiol, thioether, alcohol, ether, acid, aldehyde,ketone, amide, amidine, guanidine, sulfone, sulfonamide, sulfamide, acylsulfamide, sulfate, sulfuric acid, sulfamic acid, phosphate, phosphoricacid, boronic ester, boronic acid, squarate, squaric acid, oxime,hydrazine, peroxide, among which ether, peroxide, thioether, secondaryamine, tertiary amine, ammonium, ester, ketone, amide, amidine, oxime,hydrazine can be either acyclic or cyclic; heteroaryl is selected fromthe group consisting of furanyl, thienyl, thiazolyl, isothiazolyl,oxazolyl, isoxazolyl, imidazolyl, oxadiazolyl, thiadiazolyl, pyrazolyl,tetrazolyl, triazolyl, pyridinyl, pyrazinyl, pyridazinyl, andpyrimidinyl;J is selected from the group consisting of H, C₁-C₃₀ alkyl, C₃-C₁₅cycloalkyl, C₄-C₃₀ bicycloalkyl, C₅-C₃₀ tricycloalkyl, C₆-C₃₀tetracycloalkyl, C₃-C₃₀ alkenyl, C₄-C₃₀ cycloalkenyl, C₅-C₃₀bicycloalkenyl, C₇-C₃₀ tricycloalkenyl, C₉-C₃₀ tetracycloalkyl, C₁-C₃₀amide, C₃-C₃₀ cyclic amide, C₁-C₃₀ amine, C₃-C₃₀ cyclic amine, C₂-C₃₀ester, C₃-C₃₀ cyclic ester, C₂-C₃₀ ether, C₃-C₃₀ cyclic ether, C₁-C₃₀sulfonamide, C₃-C₃₀ cyclic sulfonamide, C₂-C₃₀ sulfone, C₃-C₃₀ cyclicsulfone, C₂-C₃₀ urea, and C₃-C₃₀ cyclic urea; wherein said C₁-C₃₀ alkyl,C₃-C₃₀ cycloalkyl, C₄-C₃₀ bicycloalkyl, C₅-C₃₀ tricycloalkyl, C₆-C₃₀tetracycloalkyl, C₃-C₃₀ alkenyl, C₄-C₃₀ cycloalkenyl, C₅-C₃₀bicycloalkenyl, C₇-C₃₀ tricycloalkenyl, C₉-C₃₀ tetracycloalkyl, C₁-C₃₀amide, C₃-C₃₀ cyclic amide, C₁-C₃₀ amine, C₃-C₃₀ cyclic amine, C₂-C₃₀ester, C₃-C₃₀ cyclic ester, C₂-C₃₀ ether, C₃-C₃₀ cyclic ether, C₁-C₃₀sulfonamide, C₃-C₃₀ cyclic sulfonamide, C₂-C₃₀ sulfone, C₃-C₃₀ cyclicsulfone, C₂-C₃₀ urea, and C₃-C₃₀ cyclic urea is optionally substitutedwith one to three same or different of the following functionalities:(C₁₋₆)alkyl, (C₃₋₆)cycloalkyl, cyano, phenyl, aryl, heteroaryl,heteroalicyclic, hydroxy, (C₁₋₆)alkoxy, halogen, benzyl, primary amine,secondary amine, tertiary amine, ammonium, nitro, thiol, thioether,alcohol, ether, acid, aldehyde, ketone, amide, amidine, guanidine,sulfone, sulfonamide, sulfamide, acyl sulfamide, sulfate, sulfuric acid,sulfamic acid, phosphate, phosphoric acid, boronic ester, boronic acid,squarate, squaric acid, oxime, hydrazine, peroxide, among which ether,peroxide, thioether, secondary amine, tertiary amine, ammonium, ester,ketone, amide, amidine, oxime, hydrazine can be either acyclic orcyclic; andR₈₁, R₈₂, R₈₃, R₈₄, R₈₅, R₈₆, and R₈₇ are each independently selectedfrom the group consisting of H, (C₁₋₆)alkyl, (C₃₋₆) cycloalkyl, (C₂₋₆)alkenyl, (C₄₋₆) cycloalkenyl, and (C₂₋₆) alkynyl.

Another embodiment of the present invention is directed to a method fortreating mammals infected with a virus, especially wherein the virus isHIV, comprising administering to said mammal an antiviral effectiveamount of a compound of Formula I above, and one or morepharmaceutically acceptable carriers, excipients or diluents.Optionally, the compound of Formula I can be administered in combinationwith an antiviral effective amount of an AIDS treatment agent selectedfrom the group consisting of: (a) an AIDS antiviral agent; (b) ananti-infective agent; (c) an immunomodulator; and (d) other HIV entryinhibitors.

Another embodiment of the present invention is a pharmaceuticalcomposition comprising an antiviral effective amount of a compound ofFormula I and one or more pharmaceutically acceptable carriers,excipients, diluents and optionally in combination with an antiviraleffective amount of an AIDS treatment agent selected from the groupconsisting of: (a) an AIDS antiviral agent; (b) an anti-infective agent;(c) an immunomodulator; and (d) other HIV entry inhibitors.

In another embodiment of the invention there is provided one or moremethods for making the compounds of Formula I.

The present invention is directed to these, as well as other importantends, hereinafter described.

DETAILED DESCRIPTION OF THE EMBODIMENTS

Since the compounds of the present invention may possess asymmetriccenters and therefore occur as mixtures of diastereomers andenantiomers, the present disclosure includes the individualdiastereoisomeric and enantiomeric forms of the compounds of Formula Iin addition to the mixtures thereof.

DEFINITIONS

Unless otherwise specifically set forth elsewhere in the application,one or more of the following terms may be used herein, and shall havethe following meanings:

The term “H” refers to hydrogen, including its isotopes such asdeuterium.

The term “C₁₋₆ alkyl” as used herein and in the claims (unless specifiedotherwise) mean straight or branched chain alkyl groups such as methyl,ethyl, propyl, isopropyl, butyl, isobutyl, t-butyl, amyl, hexyl and thelike.

“C₁-C₄ fluoroalkyl” refers to F-substituted C₁-C₄ alkyl wherein at leastone H atom is substituted with F atom, and each H atom can beindependently substituted by F atom.

“Halogen” refers to chlorine, bromine, iodine or fluorine.

An “aryl” or “Ar” group refers to an all carbon monocyclic or fused-ringpolycyclic (i.e., rings which share adjacent pairs of carbon atoms)groups having a completely conjugated pi-electron system. Examples,without limitation, of aryl groups are phenyl, napthalenyl andanthracenyl. The aryl group may be substituted or unsubstituted. Whensubstituted the substituted group(s) is preferably one or more selectedfrom alkyl, cycloalkyl, aryl, heteroaryl, heteroalicyclic, hydroxy,alkoxy, aryloxy, heteroaryloxy, heteroalicycloxy, thiohydroxy,thioaryloxy, thioheteroaryloxy, thioheteroalicycloxy, cyano, halogen,nitro, carbonyl, O-carbamyl, N-carbamyl, C-amido, N-amido, C-carboxy,O-carboxy, sulfinyl, sulfonyl, sulfonamido, trihalomethyl, ureido, aminoand —NR^(x)R^(y), wherein R^(x) and R^(y) are independently selectedfrom the group consisting of hydrogen, alkyl, cycloalkyl, aryl,carbonyl, C-carboxy, sulfonyl, trihalomethyl, and, combined, a five- orsix-member heteroalicyclic ring.

As used herein, a “heteroaryl” group refers to a monocyclic or fusedring (i.e., rings which share an adjacent pair of atoms) group having inthe ring(s) one or more atoms selected from the group consisting ofnitrogen, oxygen and sulfur and, in addition, having a completelyconjugated pi-electron system. Unless otherwise indicated, theheteroaryl group may be attached at either a carbon or nitrogen atomwithin the heteroaryl group. It should be noted that the term heteroarylis intended to encompass an N-oxide of the parent heteroaryl if such anN-oxide is chemically feasible as is known in the art. Examples, withoutlimitation, of heteroaryl groups are furyl, thienyl, benzothienyl,thiazolyl, imidazolyl, oxazolyl, oxadiazolyl, thiadiazolyl,benzothiazolyl, triazolyl, tetrazolyl, isoxazolyl, isothiazolyl,pyrrolyl, pyranyl, tetrahydropyranyl, pyrazolyl, pyridyl, pyrimidinyl,quinolinyl, isoquinolinyl, purinyl, carbazolyl, benzoxazolyl,benzimidazolyl, indolyl, isoindolyl, pyrazinyl, diazinyl, pyrazine,triazinyl, tetrazinyl, and tetrazolyl. When substituted the substitutedgroup(s) is preferably one or more selected from alkyl, cycloalkyl,aryl, heteroaryl, heteroalicyclic, hydroxy, alkoxy, aryloxy,heteroaryloxy, heteroalicycloxy, thioalkoxy, thiohydroxy, thioaryloxy,thioheteroaryloxy, thioheteroalicycloxy, cyano, halogen, nitro,carbonyl, O-carbamyl, N-carbamyl, C-amido, N-amido, C-carboxy,O-carboxy, sulfinyl, sulfonyl, sulfonamido, trihalomethyl, ureido,amino, and —NR^(x)R^(y), wherein R^(x) and R^(y) are as defined above.

As used herein, a “heteroalicyclic” group refers to a monocyclic orfused ring group having in the ring(s) one or more atoms selected fromthe group consisting of nitrogen, oxygen and sulfur. Rings are selectedfrom those which provide stable arrangements of bonds and are notintended to encompass systems which would not exist. The rings may alsohave one or more double bonds. However, the rings do not have acompletely conjugated pi-electron system. Examples, without limitation,of heteroalicyclic groups are azetidinyl, piperidyl, piperazinyl,imidazolinyl, thiazolidinyl, 3-pyrrolidin-1-yl, morpholinyl,thiomorpholinyl and tetrahydropyranyl. When substituted the substitutedgroup(s) is preferably one or more selected from alkyl, cycloalkyl,aryl, heteroaryl, heteroalicyclic, hydroxy, alkoxy, aryloxy,heteroaryloxy, heteroalicycloxy, thiohydroxy, thioalkoxy, thioaryloxy,thioheteroaryloxy, thioheteroalicycloxy, cyano, halogen, nitro,carbonyl, thiocarbonyl, O-carbamyl, N-carbamyl, O-thiocarbamyl,N-thiocarbamyl, C-amido, C-thioamido, N-amido, C-carboxy, O-carboxy,sulfinyl, sulfonyl, sulfonamido, trihalomethanesulfonamido,trihalomethanesulfonyl, silyl, guanyl, guanidino, ureido, phosphonyl,amino and —NR^(x)R^(y), wherein R^(x) and R^(y) are as defined above.

An “alkyl” group refers to a saturated aliphatic hydrocarbon includingstraight chain and branched chain groups. Preferably, the alkyl grouphas 1 to 20 carbon atoms (whenever a numerical range; e.g., “1-20”, isstated herein, it means that the group, in this case the alkyl group maycontain 1 carbon atom, 2 carbon atoms, 3 carbon atoms, etc. up to andincluding 20 carbon atoms). More preferably, it is a medium size alkylhaving 1 to 10 carbon atoms. Most preferably, it is a lower alkyl having1 to 4 carbon atoms. The alkyl group may be substituted orunsubstituted. When substituted, the substituent group(s) is preferablyone or more individually selected from trihaloalkyl, cycloalkyl, aryl,heteroaryl, heteroalicyclic, hydroxy, alkoxy, aryloxy, heteroaryloxy,heteroalicycloxy, thiohydroxy, thioalkoxy, thioaryloxy,thioheteroaryloxy, thioheteroalicycloxy, cyano, halo, nitro, carbonyl,thiocarbonyl, O-carbamyl, N-carbamyl, O-thiocarbamyl, N-thiocarbamyl,C-amido, C-thioamido, N-amido, C-carboxy, O-carboxy, sulfinyl, sulfonyl,sulfonamido, trihalomethanesulfonamido, trihalomethanesulfonyl, andcombined, a five- or six-member heteroalicyclic ring.

A “cycloalkyl” group refers to an all-carbon monocyclic or fused ring(i.e., rings which share and adjacent pair of carbon atoms) groupwherein one or more rings does not have a completely conjugatedpi-electron system. Examples, without limitation, of cycloalkyl groupsare cyclopropane, cyclobutane, cyclopentane, cyclopentene, cyclohexane,cyclohexene, cycloheptane, cycloheptene and adamantane. A cycloalkylgroup may be substituted or unsubstituted. When substituted, thesubstituent group(s) is preferably one or more individually selectedfrom alkyl, aryl, heteroaryl, heteroalicyclic, hydroxy, alkoxy, aryloxy,heteroaryloxy, heteroalicycloxy, thiohydroxy, thioalkoxy, thioaryloxy,thioheteroaryloxy, thioheteroalicycloxy, cyano, halo, nitro, carbonyl,thiocarbonyl, O-carbamyl, N-carbamyl, O-thiocarbamyl, N-thiocarbamyl,C-amido, C-thioamido, N-amido, C-carboxy, O-carboxy, sulfinyl, sulfonyl,sulfonamido, trihalomethanesulfonamido, trihalomethanesulfonyl, silyl,guanyl, guanidino, ureido, phosphonyl, amino and —NR^(x)R^(y) with R^(x)and R^(y) as defined above.

An “alkenyl” group refers to an alkyl group, as defined herein, havingat least two carbon atoms and at least one carbon-carbon double bond.

An “alkynyl” group refers to an alkyl group, as defined herein, havingat least two carbon atoms and at least one carbon-carbon triple bond.

A “hydroxy” group refers to an —OH group.

An “alkoxy” group refers to both an —O-alkyl and an —O-cycloalkyl groupas defined herein.

An “aryloxy” group refers to both an —O-aryl and an —O-heteroaryl group,as defined herein.

A “heteroaryloxy” group refers to a heteroaryl-O— group with heteroarylas defined herein.

A “heteroalicycloxy” group refers to a heteroalicyclic-O— group withheteroalicyclic as defined herein.

A “thiohydroxy” group refers to an —SH group.

A “thioalkoxy” group refers to both an S-alkyl and an —S-cycloalkylgroup, as defined herein.

A “thioaryloxy” group refers to both an —S-aryl and an —S-heteroarylgroup, as defined herein.

A “thioheteroaryloxy” group refers to a heteroaryl-S— group withheteroaryl as defined herein.

A “thioheteroalicycloxy” group refers to a heteroalicyclic-S— group withheteroalicyclic as defined herein.

A “carbonyl” group refers to a —C(═O)—R″ group, where R″ is selectedfrom the group consisting of hydrogen, alkyl, alkenyl, alkynyl,cycloalkyl, aryl, heteroaryl (bonded through a ring carbon) andheteroalicyclic (bonded through a ring carbon), as each is definedherein.

An “aldehyde” group refers to a carbonyl group where R″ is hydrogen.

A “thiocarbonyl” group refers to a —C(═S)—R″ group, with R″ as definedherein.

A “Keto” group refers to a —CC(═O)C— group wherein the carbon on eitheror both sides of the C═O may be alkyl, cycloalkyl, aryl or a carbon of aheteroaryl or heteroalicyclic group.

A “trihalomethanecarbonyl” group refers to a Z₃CC(═O)— group with said Zbeing a halogen.

A “C-carboxy” group refers to a —C(═O)O—R″ groups, with R″ as definedherein.

An “O-carboxy” group refers to a R″C(—O)O-group, with R″ as definedherein.

A “carboxylic acid” group refers to a C-carboxy group in which R″ ishydrogen.

A “trihalomethyl” group refers to a —CZ₃, group wherein Z is a halogengroup as defined herein.

A “trihalomethanesulfonyl” group refers to an Z₃CS(═O)₂— groups with Zas defined above.

A “trihalomethanesulfonamido” group refers to a Z₃CS(═O)₂NR^(x)— groupwith Z as defined above and R^(x) being H or (C₁₋₆)alkyl.

A “sulfinyl” group refers to a —S(═O)—R″ group, with R″ being(C₁₋₆)alkyl.

A “sulfonyl” group refers to a —S(═O)₂R″ group with R″ being(C₁₋₆)alkyl.

A “S-sulfonamido” group refers to a —S(═O)₂NR^(X)R^(Y), with R^(X) andR^(Y) independently being H or (C₁₋₆)alkyl.

A “N-Sulfonamido” group refers to a R″S(═O)₂NR_(X)— group, with R_(x)being H or (C₁₋₆)alkyl.

A “O-carbamyl” group refers to a —OC(═O)NR^(x)R^(y) group, with R^(X)and R^(Y) independently being H or (C₁₋₆)alkyl.

A “N-carbamyl” group refers to a R^(x)OC(═O)NR^(y) group, with R^(x) andR^(y) independently being H or (C₁₋₆)alkyl.

A “O-thiocarbamyl” group refers to a —OC(═S)NR^(x)R^(y) group, withR^(x) and R^(y) independently being H or (C₁₋₆)alkyl.

A “N-thiocarbamyl” group refers to a R^(x)OC(═S)NR^(y)— group, withR^(x) and R^(y) independently being H or (C₁₋₆)alkyl.

An “amino” group refers to an —NH₂ group.

A “C-amido” group refers to a —C(═O)NR^(x)R^(y) group, with R^(x) andR^(y) independently being H or (C₁₋₆)alkyl.

A “C-thioamido” group refers to a —C(═S)NR^(x)R^(y) group, with R^(x)and R^(y) independently being H or (C₁₋₆)alkyl.

A “N-amido” group refers to a R^(x)C(═O)NR^(y)— group, with R^(x) andR^(y) independently being H or (C₁₋₆)alkyl.

An “ureido” group refers to a —NR^(x)C(═O)NR^(y)R^(y2) group, withR^(x), R^(y), and R^(y2) independently being H or (C₁₋₆)alkyl.

A “guanidino” group refers to a —R^(x)NC(═N)NR^(y)R^(y2) group, withR^(x), R^(y), and R^(y2) independently being H or (C₁₋₆)alkyl.

A “guanyl” group refers to a R^(x)R^(y)NC(═N)— group, with R^(x) andR^(y) independently being H or (C₁₋₆)alkyl.

A “cyano” group refers to a —CN group.

A “silyl” group refers to a —Si(R″)₃, with R″ being (C₁₋₆)alkyl orphenyl.

A “phosphonyl” group refers to a P(═O)(OR^(x))₂ with R^(x) being(C₁₋₆)alkyl.

A “hydrazino” group refers to a —NR^(x)NR^(y)R^(y2) group, with R^(x),R^(y), and R^(y2) independently being H or (C₁₋₆)alkyl.

A “4, 5, or 6 membered ring cyclic N-lactam” group refers to

Any two adjacent R groups may combine to form an additional aryl,cycloalkyl, heteroaryl or heterocyclic ring fused to the ring initiallybearing those R groups.

It is known in the art that nitrogen atoms in heteroaryl systems can be“participating in a heteroaryl ring double bond”, and this refers to theform of double bonds in the two tautomeric structures which comprisefive-member ring heteroaryl groups. This dictates whether nitrogens canbe substituted as well understood by chemists in the art. The disclosureand claims of the present disclosure are based on the known generalprinciples of chemical bonding. It is understood that the claims do notencompass structures known to be unstable or not able to exist based onthe literature.

Pharmaceutically acceptable salts and prodrugs of compounds disclosedherein are within the scope of this disclosure. The term“pharmaceutically acceptable salt” as used herein and in the claims isintended to include nontoxic base addition salts. Suitable salts includethose derived from organic and inorganic acids such as, withoutlimitation, hydrochloric acid, hydrobromic acid, phosphoric acid,sulfuric acid, methanesulfonic acid, acetic acid, tartaric acid, lacticacid, sulfuric acid, citric acid, maleic acid, fumaric acid, sorbicacid, aconitic acid, salicylic acid, phthalic acid, and the like. Theterm “pharmaceutically acceptable salt” as used herein is also intendedto include salts of acidic groups, such as a carboxylate, with suchcounterions as ammonium, alkali metal salts, particularly sodium orpotassium, alkaline earth metal salts, particularly calcium ormagnesium, and salts with suitable organic bases such as loweralkylamines (methylamine, ethylamine, cyclohexylamine, and the like) orwith substituted lower alkylamines (e.g., hydroxyl-substitutedalkylamines such as diethanolamine, triethanolamine ortris(hydroxymethyl)-aminomethane), or with bases such as piperidine ormorpholine.

As stated above, the compounds of the invention also include “prodrugs”.The term “prodrug” as used herein encompasses both the term “prodrugesters” and the term “prodrug ethers”. The term “prodrug esters” asemployed herein includes esters and carbonates formed by reacting one ormore hydroxyls of compounds of Formula I with either alkyl, alkoxy, oraryl substituted acylating agents or phosphorylating agent employingprocedures known to those skilled in the art to generate acetates,pivalates, methylcarbonates, benzoates, amino acid esters, phosphates,half acid esters such as malonates, succinates or glutarates, and thelike. In certain embodiments, amino acid esters may be especiallypreferred.

Examples of such prodrug esters include

The term “prodrug ethers” include both phosphate acetals andO-glucosides. Representative examples of such prodrug ethers include

Prodrug derivatives in which the prodrug moiety is attached to theindole N atom are also considered part of this invention. These prodrugscan be prepared by substitution of the indole N with a moiety thatmodifies the physical properties of the compound and can be unmaskedeither by chemical or enzymatic degradation. Examples of R₃ include acylderivatives similar to those described above. A preferred prodrug is thephosphonoxymethyl moiety which can be introduced using methodspreviously described and converted to pharmaceutically acceptable saltforms that confer chemical stability and advantageous physicalproperties:

As set forth above, the invention is directed to compounds of Formula I,including pharmaceutically acceptable salts thereof:

wherein A is selected from the group consisting of:

whereina, b, c, d and e are independently selected from the group consisting ofhydrogen, halogen, cyano, nitro, COOR⁵⁶, XR⁵⁷, NA¹A², C(O)R⁷,C(O)NR⁵⁵R⁵⁶, B, Q, and E;B is selected from the group consisting of —C(═NR⁴⁶)(R⁴⁷), C(O)NR⁴⁰R⁴¹,aryl, heteroaryl, heteroalicyclic, S(O)₂R⁸, C(O)R⁷, XR^(8a),(C₁₋₆)alkylNR⁴⁰R⁴¹, (C₁₋₆)alkylCOOR^(8b); wherein said aryl, heteroaryl,and heteroalicyclic are optionally substituted with one to three same ordifferent halogens or from one to three same or different substituentsselected from the group F; wherein aryl is napthyl or substitutedphenyl; wherein heteroaryl is a mono or bicyclic system which containsfrom 3 to 7 ring atoms for a mono cyclic system and up to 12 atoms in afused bicyclic system, including from 1 to 4 heteroatoms; whereinheteroalicyclic is a 3 to 7 membered mono cyclic ring which may containfrom 1 to 2 heteroatoms in the ring skeleton and which may be fused to abenzene or pyridine ring;Q is selected from the group consisting of (C₁₋₆)alkyl and(C₂₋₆)alkenyl; wherein said (C₁₋₆)alkyl and (C₂₋₆)alkenyl are optionallysubstituted with one to three same or different halogens or from one tothree same or different substituents selected from the group consistingof C(O)NR⁵⁵R⁵⁶, hydroxy, cyano and XR⁵⁷;E is selected from the group consisting of (C₁₋₆)alkyl and(C₂₋₆)alkenyl; wherein said (C₁₋₆)alkyl and (C₂₋₆)alkenyl areindependently optionally substituted with a member selected from thegroup consisting of phenyl, heteroaryl, SMe, SPh,—C(O)NR₅₆R₅₇, C(O)R₅₇, SO₂(C₁₋₆)alkyl and SO₂Ph; wherein heteroaryl is amonocyclic system which contains from 3 to 7 ring atoms, including from1 to 4 heteroatoms;R⁷ is selected from the group consisting of aryl, heteroaryl, andheteroalicyclic; wherein said aryl, heteroaryl, and heteroalicyclic areoptionally substituted with one to three same or different halogens orwith from one to three same or different substituents selected from thegroup F;wherein for R⁷, R⁸, R^(8a), R^(8b) aryl is phenyl; heteroaryl is a monoor bicyclic system which contains from 3 to 7 ring atoms for mono cyclicsystems and up to 10 atoms in a bicyclic system, including from 1 to 4heteroatoms; wherein heteroalicyclic is selected from the groupconsisting of aziridine, azetidine, pyrrolidine, piperazine, piperidine,tetrahydrofuran, tetrahydropyran, azepine, and morpholine;F is selected from the group consisting of (C₁₋₆)alkyl,(C₃₋₇)cycloalkyl, aryl, heteroaryl, heteroalicyclic, hydroxy,(C₁₋₆)alkoxy, aryloxy, (C₁₋₆)thioalkoxy, cyano, halogen, nitro,—C(O)R⁵⁷, benzyl, —NR⁴²C(O)—(C₁₋₆)alkyl, —NR⁴²C(O)—(C₃₋₆)cycloalkyl,—NR⁴²C(O)-aryl, —NR⁴²C(O)-heteroaryl, —NR⁴²C(O)-heteroalicyclic, a 4, 5,or 6 membered ring cyclic N-lactam, —NR⁴²S(O)₂—(C₁₋₆)alkyl,—NR⁴²S(O)₂—(C₃₋₆)cycloalkyl, —NR⁴²S(O)2-aryl, —NR⁴²S(O)₂-heteroaryl,—NR⁴²S(O)2-heteroalicyclic, S(O)₂(C₁₋₆)alkyl, S(O)₂aryl, —S(O)2 NR⁴²R⁴³,NR⁴²R⁴³, (C₁₋₆)alkylC(O)NR⁴²R⁴³, C(O)NR⁴²R⁴³, NHC(O)NR⁴²R⁴³,OC(O)NR⁴²R⁴³, NHC(O)OR⁵⁴, (C₁₋₆)alkylNR⁴²R⁴³, COOR⁵⁴, and(C₁₋₆)alkylCOOR⁵⁴; wherein said (C₁₋₆)alkyl, (C₃₋₇)cycloalkyl, aryl,heteroaryl, heteroalicyclic, (C₁₋₆)alkoxy, and aryloxy, are optionallysubstituted with one to nine same or different halogens or from one tofive same or different substituents selected from the group G; whereinaryl is phenyl; heteroaryl is a monocyclic system which contains from 3to 7 ring atoms, including from 1 to 4 heteroatoms; heteroalicyclic isselected from the group consisting of aziridine, azetidine, pyrrolidine,piperazine, piperidine, tetrahydrofuran, tetrahydropyran, azepine, andmorpholine;R⁸ is selected from the group consisting of hydrogen, (C₁₋₆)alkyl,(C₃₋₇)cycloalkyl, (C₂₋₆)alkenyl, (C₃₋₇)cycloalkenyl, (C₂₋₆)alkynyl,aryl, heteroaryl, and heteroalicyclic; wherein said (C₁₋₆)alkyl,(C₃₋₇)cycloalkyl, (C₂₋₆)alkenyl, (C₃₋₇)cycloalkenyl, (C₂₋₆)alkynyl,aryl, heteroaryl, and heteroalicyclic are optionally substituted withone to six same or different halogens or from one to five same ordifferent substituents selected from the group F or (C₁₋₆)alkyl,(C₃₋₆)cycloalkyl, cyano, phenyl, aryl, heteroaryl, heteroalicyclic,hydroxy, (C₁₋₆)alkoxy, halogen, benzyl, primary amine, secondary amine,tertiary amine, ammonium, nitro, thiol, thioether, alcohol, ether, acid,aldehyde, ketone, amide, amidine, guanidine, sulfone, sulfonamide,sulfamide, acyl sulfamide, sulfate, sulfuric acid, sulfamic acid,phosphate, phosphoric acid, boronic ester, boronic acid, squarate,squaric acid, oxime, hydrazine, peroxide, among which ether, peroxide,thioether, secondary amine, tertiary amine, ammonium, ester, ketone,amide, amidine, oxime, hydrazine can be either acyclic or cyclic;heteroaryl is selected from the group consisting of furanyl, thienyl,thiazolyl, isothiazolyl, oxazolyl, isoxazolyl, imidazolyl, oxadiazolyl,thiadiazolyl, pyrazolyl, tetrazolyl, triazolyl, pyridinyl, pyrazinyl,pyridazinyl, and pyrimidinyl;R^(8a) is a member selected from the group consisting of aryl,heteroaryl, and heteroalicyclic; wherein each member is independentlyoptionally substituted with one to six same or different halogens orfrom one to five same or different substituents selected from the groupF;R^(8b) is selected from the group consisting of hydrogen, (C₁₋₆)alkyland phenyl;X is selected from the group consisting of NH or NCH₃, O, and S;R⁴⁰ and R⁴¹ are independently selected from the group consisting of(a) hydrogen; (b) (C₁₋₆)alkyl or (C₃₋₇)cycloalkyl substituted with oneto three same or different halogens or from one to two same or differentsubstituents selected from the group F or different functional groups:(C₁₋₆)alkyl, (C₃₋₆)cycloalkyl, cyano, phenyl, aryl, heteroaryl,heteroalicyclic, hydroxy, (C₁₋₆)alkoxy, halogen, benzyl, primary amine,secondary amine, tertiary amine, ammonium, nitro, thiol, thioether,alcohol, ether, acid, aldehyde, ketone, amide, amidine, guanidine,sulfone, sulfonamide, sulfamide, acyl sulfamide, sulfate, sulfuric acid,sulfamic acid, phosphate, phosphoric acid, boronic ester, boronic acid,squarate, squaric acid, oxime, hydrazine, peroxide, among which ether,peroxide, thioether, secondary amine, tertiary amine, ammonium, ester,ketone, amide, amidine, oxime, hydrazine can be either acyclic orcyclic; heteroaryl is selected from the group consisting of furanyl,thienyl, thiazolyl, isothiazolyl, oxazolyl, isoxazolyl, imidazolyl,oxadiazolyl, thiadiazolyl, pyrazolyl, tetrazolyl, triazolyl, pyridinyl,pyrazinyl, pyridazinyl, and pyrimidinyl; and (c) (C₁₋₆)alkoxy, aryl,heteroaryl or heteroalicyclic; or R⁴⁰ and R⁴¹ taken together with thenitrogen to which they are attached form a member selected from thegroup consisting of aziridine, azetidine, pyrrolidine, piperazine, 4—NMepiperazine, piperidine, azepine, and morpholine; and wherein said aryl,heteroaryl, and heteroalicyclic are optionally substituted with one tothree same or different halogens or from one to two same or differentsubstituents selected from the group F; wherein for R⁴⁰ and R⁴¹ aryl isphenyl; heteroaryl is a monocyclic system which contains from 3 to 6ring atoms, including from 1 to 4 heteroatoms; heteroalicyclic isselected from the group consisting of aziridine, azetidine, pyrrolidine,piperazine, piperidine, tetrahydrofuran, tetrahydropyran, azepine, andmorpholine; provided when B is C(O)NR⁴⁰R⁴¹, at least one of R⁴⁰ and R⁴¹is not selected from groups (a) or (b);R⁴² and R⁴³ are independently selected from the group consisting ofhydrogen, (C₁₋₆)alkyl, allyl, (C₁₋₆)alkoxy, (C₃₋₇)cycloalkyl, aryl,heteroaryl and heteroalicyclic; or R⁴² and R⁴³ taken together with thenitrogen to which they are attached form a member selected from thegroup consisting of aziridine, azetidine, pyrrolidine, piperazine, 4—NMepiperazine, piperidine, azepine, and morpholine; and wherein said(C₁₋₆)alkyl, (C₁₋₆)alkoxy, (C₃₋₇)cycloalkyl, aryl, heteroaryl, andheteroalicyclic are optionally substituted with one to three same ordifferent halogens or from one to two same or different substituentsselected from the group G or different functional groups: (C₁₋₆)alkyl,(C₃₋₆)cycloalkyl, cyano, phenyl, aryl, heteroaryl, heteroalicyclic,hydroxy, (C₁₋₆)alkoxy, halogen, benzyl, primary amine, secondary amine,tertiary amine, ammonium, nitro, thiol, thioether, alcohol, ether, acid,aldehyde, ketone, amide, amidine, guanidine, sulfone, sulfonamide,sulfamide, acyl sulfamide, sulfate, sulfuric acid, sulfamic acid,phosphate, phosphoric acid, boronic ester, boronic acid, squarate,squaric acid, oxime, hydrazine, peroxide, among which ether, peroxide,thioether, secondary amine, tertiary amine, ammonium, ester, ketone,amide, amidine, oxime, hydrazine can be either acyclic or cyclic;heteroaryl is selected from the group consisting of furanyl, thienyl,thiazolyl, isothiazolyl, oxazolyl, isoxazolyl, imidazolyl, oxadiazolyl,thiadiazolyl, pyrazolyl, tetrazolyl, triazolyl, pyridinyl, pyrazinyl,pyridazinyl, and pyrimidinyl; wherein for R⁴² and R⁴³ aryl is phenyl;heteroaryl is a monocyclic system which contains from 3 to 6 ring atoms,including from 1 to 4 heteroatoms; heteroalicyclic is a member selectedfrom the group consisting of aziridine, azetidine, pyrrolidine,piperazine, piperidine, tetrahydrofuran, tetrahydropyran, azepine, andmorpholine;G is selected from the group consisting of (C₁₋₆)alkyl,(C₃₋₇)cycloalkyl, aryl, heteroaryl, heteroalicyclic, hydroxy,(C₁₋₆)alkoxy, aryloxy, cyano, halogen, nitro, —C(O)R⁵⁷, benzyl,—NR⁴⁸C(O)—(C₁₋₆)alkyl, —NR⁴⁸C(O)—(C₃₋₆)cycloalkyl, —NR⁴⁸C(O)-aryl,—NR⁴⁸C(O)-heteroaryl, —NR⁴⁸C(O)-heteroalicyclic, a 4, 5, or 6 memberedring cyclic N-lactam, —NR⁴⁸S(O)₂—(C₁₋₆)alkyl,—NR⁴⁸S(O)₂—(C₃₋₆)cycloalkyl, —NR⁴⁸S(O)2-aryl, —NR⁴⁸S(O)₂-heteroaryl,—NR⁴⁸S(O)2-heteroalicyclic, sulfinyl, sulfonyl, sulfonamide, NR⁴⁸R⁴⁹,(C₁₋₆)alkyl C(O)NR⁴⁸R⁴⁹, C(O)NR⁴⁸R⁴⁹, NHC(O)NR⁴⁸R⁴⁹, OC(O)NR⁴⁸R⁴⁹,NHC(O)OR^(54′), (C₁₋₆)alkylNR⁴⁸R⁴⁹, COOR⁵⁴, and (C₁₋₆)alkylCOOR⁵⁴;wherein aryl is phenyl; heteroaryl is a monocyclic system which containsfrom 3 to 7 ring atoms, including from 1 to 4 heteroatoms;heteroalicyclic is selected from the group consisting of aziridine,azetidine, pyrrolidine, piperazine, piperidine, tetrahydrofuran,tetrahydropyran, azepine, and morpholine;R⁴⁶ is selected from the group consisting of H, OR⁵⁷, and NR⁵⁵R⁵⁶;R⁴⁷ is selected from the group consisting of H, amino, halogen, phenyl,aryl, heteroaryl and (C₁₋₆)alkyl;R⁴⁸ and R⁴⁹ are independently selected from the group consisting ofhydrogen,(C₁₋₆)alkyl, phenyl, aryl and heteroaryl;R⁵⁰ is selected from the group consisting of H, (C₁₋₆)alkyl,(C₃₋₆)cycloalkyl, and benzyl; wherein each of said (C₁₋₆)alkyl,(C₃₋₇)cycloalkyl and benzyl are optionally substituted with one to threesame or different (C₁₋₆)alkyl, (C₃₋₆)cycloalkyl, cyano, phenyl, aryl,heteroaryl, heteroalicyclic, hydroxy, (C₁₋₆)alkoxy, halogen, benzyl,primary amine, secondary amine, tertiary amine, ammonium, nitro, thiol,thioether, alcohol, ether, acid, aldehyde, ketone, amide, amidine,guanidine, sulfone, sulfonamide, sulfamide, acyl sulfamide, sulfate,sulfuric acid, sulfamic acid, phosphate, phosphoric acid, boronic ester,boronic acid, squarate, squaric acid, oxime, hydrazine, peroxide, amongwhich ether, peroxide, thioether, secondary amine, tertiary amine,ammonium, ester, ketone, amide, amidine, oxime, hydrazine can be eitheracyclic or cyclic; heteroaryl is selected from the group consisting offuranyl, thienyl, thiazolyl, isothiazolyl, oxazolyl, isoxazolyl,imidazolyl, oxadiazolyl, thiadiazolyl, pyrazolyl, tetrazolyl, triazolyl,pyridinyl, pyrazinyl, pyridazinyl, and pyrimidinylR⁵⁴ is selected from the group consisting of hydrogen and (C₁₋₆)alkyl;R^(54′) is (C₁₋₆)alkyl;R⁵⁵ and R⁵⁶ are independently selected from the group consisting ofhydrogen and (C₁₋₆)alkyl; andR⁵⁷ is selected from the group consisting of hydrogen, (C₁₋₆)alkyl,aryl, heteroaryl; andA¹ and A² are independently selected from hydrogen, (C₁₋₆)alkyl, aryl,heteroaryl, SO2D¹, SO2ND²D³, COD⁴, COCOD⁴, COOD⁴, COND⁵D⁶, COCOND⁵D⁶,COCOOD⁴, C(═ND⁷)D⁸, C(═ND⁹)ND¹⁰D¹¹;A¹ and A² can either never connect with each other, or conjoin to form aring structure;D¹, D², D³, D⁴, D⁵, D⁶, D⁷, D⁸, D⁹, D¹⁰, and D¹¹ are each independentlyselected from the group consisting of H, C₁-C₅₀ alkyl, C₃-C₅₀cycloalkyl, C₃-C₅₀ alkenyl, C₄-C₅₀ cycloalkenyl, phenyl, heteroaryl,C₃-C₅₀ amide and C₃-C₅₀ ether; heteroaryl is selected from the groupconsisting of pyridinyl, pyrazinyl, pyridazinyl, pyrimidinyl, furanyl,thienyl, benzothienyl, thiazolyl, isothiazolyl, oxazolyl, benzooxazolyl,isoxazolyl, imidazolyl, benzoimidazolyl, 1H-imidazo[4,5-b]pyridin-2-yl,1H-imidazo[4,5-c]pyridin-2-yl, oxadiazolyl, thiadiazolyl, pyrazolyl,tetrazolyl, tetrazinyl, triazinyl and triazolyl; provided the carbonatoms which comprise the carbon-carbon double bond of said C₃-C₂₀alkenyl or the carbon-carbon triple bond of said C₃-C₂₀ alkynyl are notthe point of attachment to the nitrogen to which D², D³, D⁵, D⁶, D⁷, D⁹,D¹⁰, and D¹¹ is attached; wherein said C₁-C₅₀ alkyl, C₃-C₅₀ cycloalkyl,C₃-C₅₀ alkenyl, C₄-C₅₀ cycloalkenyl, aryl, phenyl, heteroaryl, C₃-C₅₀amide and C₃-C₅₀ ether is optionally substituted with one to three sameor different of the following functionalities: (C₁₋₆)alkyl,(C₃₋₆)cycloalkyl, cyano, phenyl, aryl, heteroaryl, heteroalicyclic,hydroxy, (C₁₋₆)alkoxy, halogen, benzyl, primary amine, secondary amine,tertiary amine, ammonium, nitro, thiol, thioether, alcohol, ether, acid,aldehyde, ketone, amide, amidine, guanidine, sulfone, sulfonamide,sulfamide, acyl sulfamide, sulfate, sulfuric acid, sulfamic acid,phosphate, phosphoric acid, boronic ester, boronic acid, squarate,squaric acid, oxime, hydrazine, peroxide, among which ether, peroxide,thioether, secondary amine, tertiary amine, ammonium, ester, ketone,amide, amidine, oxime, hydrazine can be either acyclic or cyclic;

I₁, I₂, I₃, I₄, I₅, I₆, I₇ and I₈ are each independently selected fromthe group consisting of H, (C₁₋₆)alkyl, (C₃₋₆) cycloalkyl, (C₂₋₆)alkenyl, (C₄₋₆) cycloalkenyl, (C₂₋₆) alkynyl, CR₈₁R₈₂OR₈₃, COR₈₄,COOR₈₅, or CONR₈₆R₈₇; wherein each of said alkyl and cycloalkyl beingoptionally substituted with one to three same or different cyano,phenyl, aryl, heteroaryl, heteroalicyclic, hydroxy, (C₁₋₆)alkoxy,halogen, benzyl, primary amine, secondary amine, tertiary amine,ammonium, nitro, thiol, thioether, alcohol, ether, acid, aldehyde,ketone, amide, amidine, guanidine, sulfone, sulfonamide, sulfamide, acylsulfamide, sulfate, sulfuric acid, sulfamic acid, phosphate, phosphoricacid, boronic ester, boronic acid, squarate, squaric acid, oxime,hydrazine, peroxide, among which ether, peroxide, thioether, secondaryamine, tertiary amine, ammonium, ester, ketone, amide, amidine, oxime,hydrazine can be either acyclic or cyclic; heteroaryl is selected fromthe group consisting of furanyl, thienyl, thiazolyl, isothiazolyl,oxazolyl, isoxazolyl, imidazolyl, oxadiazolyl, thiadiazolyl, pyrazolyl,tetrazolyl, triazolyl, pyridinyl, pyrazinyl, pyridazinyl, andpyrimidinyl;

J is selected from the group consisting of H, C₁-C₃₀ alkyl, C₃-C₁₅cycloalkyl, C₄-C₃₀ bicycloalkyl, C₅-C₃₀ tricycloalkyl, C₆-C₃₀tetracycloalkyl, C₃-C₃₀ alkenyl, C₄-C₃₀ cycloalkenyl, C₅-C₃₀bicycloalkenyl, C₂-C₃₀ tricycloalkenyl, C₉-C₃₀ tetracycloalkyl, C₁-C₃₀amide, C₃-C₃₀ cyclic amide, C₁-C₃₀ amine, C₃-C₃₀ cyclic amine, C₂-C₃₀ester, C₃-C₃₀ cyclic ester, C₂-C₃₀ ether, C₃-C₃₀ cyclic ether, C₁-C₃₀sulfonamide, C₃-C₃₀ cyclic sulfonamide, C₂-C₃₀ sulfone, C₃-C₃₀ cyclicsulfone, C₂-C₃₀ urea, and C₃-C₃₀ cyclic urea; wherein said C₁-C₃₀ alkyl,C₃-C₃₀ cycloalkyl, C₄-C₃₀ bicycloalkyl, C₅-C₃₀ tricycloalkyl, C₆-C₃₀tetracycloalkyl, C₃-C₃₀ alkenyl, C₄-C₃₀ cycloalkenyl, C₅-C₃₀bicycloalkenyl, C₇-C₃₀ tricycloalkenyl, C₉-C₃₀ tetracycloalkyl, C₁-C₃₀amide, C₃-C₃₀ cyclic amide, C₁-C₃₀ amine, C₃-C₃₀ cyclic amine, C₂-C₃₀ester, C₃-C₃₀ cyclic ester, C₂-C₃₀ ether, C₃-C₃₀ cyclic ether, C₁-C₃₀sulfonamide, C₃-C₃₀ cyclic sulfonamide, C₂-C₃₀ sulfone, C₃-C₃₀ cyclicsulfone, C₂-C₃₀ urea, and C₃-C₃₀ cyclic urea is optionally substitutedwith one to three same or different of the following functionalities:(C₁₋₆)alkyl, (C₃₋₆)cycloalkyl, cyano, phenyl, aryl, heteroaryl,heteroalicyclic, hydroxy, (C₁₋₆)alkoxy, halogen, benzyl, primary amine,secondary amine, tertiary amine, ammonium, nitro, thiol, thioether,alcohol, ether, acid, aldehyde, ketone, amide, amidine, guanidine,sulfone, sulfonamide, sulfamide, acyl sulfamide, sulfate, sulfuric acid,sulfamic acid, phosphate, phosphoric acid, boronic ester, boronic acid,squarate, squaric acid, oxime, hydrazine, peroxide, among which ether,peroxide, thioether, secondary amine, tertiary amine, ammonium, ester,ketone, amide, amidine, oxime, hydrazine can be either acyclic orcyclic; andR₈₁, R₈₂, R₈₃, R₈₄, R₈₅, R₈₆, and R₈₇ are each independently selectedfrom the group consisting of H, (C₁₋₆)alkyl, (C₃₋₆) cycloalkyl, (C₂₋₆)alkenyl, (C₄₋₆) cycloalkenyl, and (C₂₋₆) alkynyl.

In a further embodiment of the compounds of Formula I above, there isthe proviso that at least one of a-e is selected from group B or groupE.

In a further embodiment, it is preferred that A be selected from thegroup consisting of:

In another embodiment, it is preferred that B is selected from the groupconsisting of C(O)NR⁴⁰R⁴¹, aryl, heteroaryl, and XR^(8a).

In another embodiment, it is preferred that Q is (C₁₋₆)alkyl.

In a further embodiment, it is preferred that E is (C₂₋₆)alkenyl;optionally substituted with a member selected from the group consistingof phenyl, heteroaryl, —C(O)NR⁵⁶R⁵⁷, and —C(O)R⁵⁷.

In another embodiment, it is preferred that R⁷ is selected from thegroup of phenyl, pyridinyl, pyrazinyl, pyridazinyl, pyrimidinyl,thiazolyl, isothiazolyl, oxazolyl, isoxazolyl, imidazolyl, oxadiazolyl,thiadiazolyl, pyrazolyl, tetrazolyl, triazinyl and triazolyl; whereinsaid phenyl, pyridinyl, pyrazinyl, pyridazinyl, pyrimidinyl, thiazolyl,isothiazolyl, oxazolyl, isoxazolyl, imidazolyl, oxadiazolyl,thiadiazolyl, pyrazolyl, tetrazolyl, triazinyl and triazolyl areoptionally substituted with one to three same or different halogens orwith from one to three same or different substituents selected from thegroup F.

In another embodiment, it is preferred that F is selected from the groupconsisting of (C₁₋₆)alkyl, (C₃₋₇)cycloalkyl, hydroxy, (C₁₋₆)alkoxy,cyano, halogen, —NR⁴²C(O)—(C₁₋₆)alkyl, —NR⁴²C(O)—(C₃₋₆)cycloalkyl, a 4,5, or 6 membered ring cyclic N-lactam, —NR⁴²S(O)₂—(C₁₋₆)alkyl,—NR⁴²S(O)₂—(C₃₋₆)cycloalkyl, S(O)₂(C₁₋₆)alkyl, —S(O)2 NR⁴²R⁴³, NR⁴²R⁴³,(C₁₋₆)alkylC(O)NR⁴²R⁴³, C(O)NR⁴²R⁴³, NHC(O)NR⁴²R⁴³, OC(O)NR⁴²R⁴³,NHC(O)OR⁵⁴, (C₁₋₆)alkylNR⁴²R⁴³, COOR⁵⁴, and (C₁₋₆)alkylCOOR⁵⁴.

In another embodiment, it is preferred that X be NH, NCH₃, or O.

In another embodiment, it is preferred that R⁴⁰ and R⁴¹ be selected fromthe group of (a) hydrogen; (b) (C₁₋₆)alkyl or (C₃₋₇)cycloalkylsubstituted with one to three same or different halogens or from one totwo same or different substituents selected from the group F ordifferent functional groups: (C₁₋₆)alkyl, (C₃₋₆)cycloalkyl, phenyl,aryl, heteroaryl, heteroalicyclic, hydroxy, (C₁₋₆)alkoxy, halogen,primary amine, secondary amine, tertiary amine, ammonium, alcohol,ether, acid, ketone, amide, amidine, guanidine, sulfone, sulfonamide,sulfamide, acyl sulfamide, sulfate, sulfuric acid, sulfamic acid,phosphate, phosphoric acid, boronic ester, boronic acid, squarate,squaric acid, oxime, hydrazine, among which ether, secondary amine,tertiary amine, ammonium, ester, ketone, amide, amidine, oxime,hydrazine can be either acyclic or cyclic; heteroaryl is selected fromthe group consisting of thiazolyl, isothiazolyl, oxazolyl, isoxazolyl,imidazolyl, oxadiazolyl, thiadiazolyl, pyrazolyl, tetrazolyl, triazolyl,pyridinyl, pyrazinyl, pyridazinyl, and pyrimidinyl; and (c)(C₁₋₆)alkoxy, aryl, heteroaryl or heteroalicyclic; or R⁴⁰ and R⁴¹ takentogether with the nitrogen to which they are attached form a memberselected from the group consisting of azetidine, pyrrolidine,piperazine, 4—NMe piperazine, piperidine, azepine, and morpholine; andwherein said aryl, heteroaryl, and heteroalicyclic are optionallysubstituted with one to three same or different halogens or from one totwo same or different substituents selected from the group F; whereinfor R⁴⁰ and R⁴¹ aryl is phenyl; heteroaryl is a monocyclic system whichcontains from 3 to 6 ring atoms, including from 1 to 4 heteroatoms;heteroalicyclic is selected from the group consisting of azetidine,pyrrolidine, piperazine, piperidine, tetrahydrofuran, tetrahydropyran,azepine, and morpholine; provided when B is C(O)NR⁴⁰R⁴¹, at least one ofR⁴⁰ and R⁴¹ is not selected from groups (a) or (b).

In a further embodiment, it is preferred that R⁴² and R⁴³ be selectedfrom the group of hydrogen, (C₁₋₆)alkyl, a (C₁₋₆)alkoxy,(C₃₋₇)cycloalkyl, aryl, heteroaryl and heteroalicyclic; or R⁴² and R⁴³taken together with the nitrogen to which they are attached form amember selected from the group consisting of azetidine, pyrrolidine,piperazine, 4—NMe piperazine, piperidine, azepine, and morpholine; andwherein said (C₁₋₆)alkyl, (C₁₋₆)alkoxy, (C₃₋₇)cycloalkyl, aryl,heteroaryl, and heteroalicyclic are optionally substituted with one tothree same or different halogens or from one to two same or differentsubstituents selected from the group G or different functional groups:(C₁₋₆)alkyl, (C₃₋₆)cycloalkyl, phenyl, aryl, heteroaryl,heteroalicyclic, hydroxy, (C₁₋₆)alkoxy, halogen, benzyl, primary amine,secondary amine, tertiary amine, ammonium, alcohol, ether, acid, ketone,amide, amidine, guanidine, sulfone, sulfonamide, sulfamide, acylsulfamide, sulfate, sulfuric acid, sulfamic acid, phosphate, phosphoricacid, boronic ester, boronic acid, squarate, squaric acid, oxime,hydrazine, among which ether, secondary amine, tertiary amine, ammonium,ester, ketone, amide, amidine, oxime, hydrazine can be either acyclic orcyclic; heteroaryl is selected from the group consisting of thiazolyl,isothiazolyl, oxazolyl, isoxazolyl, imidazolyl, oxadiazolyl,thiadiazolyl, pyrazolyl, tetrazolyl, triazolyl, pyridinyl, pyrazinyl,pyridazinyl, and pyrimidinyl; wherein for R⁴² and R⁴³ aryl is phenyl;heteroaryl is a monocyclic system which contains from 3 to 6 ring atoms,including from 1 to 4 heteroatoms; heteroalicyclic is a member selectedfrom the group consisting of azetidine, pyrrolidine, piperazine,piperidine, tetrahydrofuran, tetrahydropyran, azepine, and morpholine.

In another embodiment, it is preferred that G is selected from the groupconsisting of (C₁₋₆)alkyl, (C₃₋₇)cycloalkyl, hydroxy, (C₁₋₆)alkoxy,cyano, halogen, —NR⁴²C(O)—(C₁₋₆)alkyl, —NR⁴²C(O)—(C₃₋₆)cycloalkyl, a 4,5, or 6 membered ring cyclic N-lactam, —NR⁴²S(O)₂—(C₁₋₆)alkyl,—NR⁴²S(O)₂—(C₃₋₆)cycloalkyl, S(O)₂(C₁₋₆)alkyl, —S(O)2 NR⁴²R⁴³, NR⁴²R⁴³,(C₁₋₆)alkylC(O)NR⁴²R⁴³, C(O)NR⁴²R⁴³, NHC(O)NR⁴²R⁴³, OC(O)NR⁴²R⁴³,NHC(O)OR⁵⁴, (C₁₋₆)alkylNR⁴²R⁴³, COOR⁵⁴, and (C₁₋₆)alkylCOOR⁵⁴.

In a further embodiment, it is preferred that A¹ and A² be selected fromthe group consisting of hydrogen, (C₁₋₆)alkyl, aryl, heteroaryl, COD⁴,COCOD⁴, COOD⁴, COND⁵D⁶, COCOND⁵D⁶, and COCOOD⁴.

In another embodiment, it is preferred that D⁴, D⁵, and D⁶ be selectedfrom the group consisting of H, C₁-C₁₀ alkyl, C₃-C₁₀ cycloalkyl, C₃-C₁₀alkenyl, C₄-C₁₀ cycloalkenyl, phenyl, heteroaryl, C₃-C₁₀ amide andC₃-C₁₀ ether; heteroaryl is selected from the group consisting ofpyridinyl, pyrazinyl, pyridazinyl, pyrimidinyl, thiazolyl, isothiazolyl,oxazolyl, isoxazolyl, imidazolyl, oxadiazolyl, thiadiazolyl, pyrazolyl,tetrazolyl, triazinyl and triazolyl; provided the carbon atoms whichcomprise the carbon-carbon double bond of said C₃-C₁₀ alkenyl or thecarbon-carbon triple bond of said C₃-C₁₀ alkynyl are not the point ofattachment to the nitrogen to which D⁵ and D⁶ is attached; wherein saidC₁-C₁₀ alkyl, C₃-C₁₀ cycloalkyl, C₃-C₁₀ alkenyl, C₄-C₁₀ cycloalkenyl,aryl, phenyl, heteroaryl, C₃-C₁₀ amide and C₃-C₁₀ ether is optionallysubstituted with one to three same or different of the followingfunctionalities: (C₁₋₆)alkyl, (C₃₋₆)cycloalkyl, cyano, phenyl, aryl,heteroaryl, heteroalicyclic, hydroxy, (C₁₋₆)alkoxy, halogen, primaryamine, secondary amine, tertiary amine, ammonium, alcohol, ether, acid,ketone, amide, amidine, guanidine, sulfone, sulfonamide, sulfamide, acylsulfamide, sulfate, sulfuric acid, sulfamic acid, phosphate, phosphoricacid, boronic ester, boronic acid, squarate, squaric acid, oxime,hydrazine, peroxide, among which ether, thioether, secondary amine,tertiary amine, ammonium, ester, ketone, amide, amidine, oxime,hydrazine can be either acyclic or cyclic.

In another embodiment, it is preferred that I₁, I₂, I₃, I₄, I₅, I₆, I₇and I₈ are selected from the group of H, (C₁₋₆)alkyl, (C₃₋₆) cycloalkyl,(C₂₋₆) alkenyl, CR₈₁R₈₂OR₈₃, COR₈₄, COOR₈₅, and CONR₈₆R₈₇.

In a further embodiment, it is preferred that J be selected from thegroup consisting of H, C₁-C₁₀ alkyl, C₃-C₁₀ cycloalkyl, C₄-C₁₅bicycloalkyl, C₅-C₂₀ tricycloalkyl, C₆-C₂₅ tetracycloalkyl, C₃-C₁₀alkenyl, C₄-C₁₀ cycloalkenyl, C₅-C₁₅ bicycloalkenyl, C₇-C₂₀tricycloalkenyl, C₉-C₂₅ tetracycloalkyl, C₁-C₁₀ amide, C₃-C₁₀ cyclicamide, C₁-C₁₀ amine, C₃-C₁₀ cyclic amine, C₂-C₁₀ ester, C₃-C₁₀ cyclicester, C₂-C₁₀ ether, C₃-C₁₀ cyclic ether, C₁-C₁₀ sulfonamide, C₃-C₁₀cyclic sulfonamide, C₂-C₁₀ sulfone, C₃-C₁₀ cyclic sulfone, C₂-C₁₀ urea,and C₃-C₁₀ cyclic urea; wherein said H, C₁-C₁₀ alkyl, C₃-C₁₀ cycloalkyl,C₄-C₁₅ bicycloalkyl, C₅-C₂₀ tricycloalkyl, C₆-C₂₅ tetracycloalkyl,C₃-C₁₀ alkenyl, C₄-C₁₀ cycloalkenyl, C₅-C₁₅ bicycloalkenyl, C₇-C₂₀tricycloalkenyl, C₉-C₂₅ tetracycloalkyl, C₁-C₁₀ amide, C₃-C₁₀ cyclicamide, C₁-C₁₀ amine, C₃-C₁₀ cyclic amine, C₂-C₁₀ ester, C₃-C₁₀ cyclicester, C₂-C₁₀ ether, C₃-C₁₀ cyclic ether, C₁-C₁₀ sulfonamide, C₃-C₁₀cyclic sulfonamide, C₂-C₁₀ sulfone, C₃-C₁₀ cyclic sulfone, C₂-C₁₀ urea,and C₃-C₁₀ cyclic urea is optionally substituted with one to three sameor different of the following functionalities: (C₁₋₆)alkyl,(C₃₋₆)cycloalkyl, cyano, phenyl, aryl, heteroaryl, heteroalicyclic,hydroxy, (C₁₋₆)alkoxy, halogen, primary amine, secondary amine, tertiaryamine, ammonium, alcohol, ether, acid, ketone, amide, amidine,guanidine, sulfone, sulfonamide, sulfamide, acyl sulfamide, sulfate,phosphate, squarate, oxime, among which ether, secondary amine, tertiaryamine, ammonium, ester, ketone, amide, amidine, oxime, can be eitheracyclic or cyclic.

In addition, it is preferred that R₈₁, R₈₂, R₈₃, R₈₄, R₈₅, R₈₆, and R₈₇be selected from the group consisting of H, (C₁₋₆)alkyl and (C₃₋₆)cycloalkyl.

More preferred compounds of Formula I include those which are selectedfrom the group consisting of:

The compounds of the present invention, according to all the variousembodiments described above, may be administered orally, parenterally(including subcutaneous injections, intravenous, intramuscular,intrasternal injection or infusion techniques), by inhalation spray, orrectally, and by other means, in dosage unit formulations containingnon-toxic pharmaceutically acceptable carriers, excipients and diluentsavailable to the skilled artisan. One or more adjuvants may also beincluded.

Thus, in accordance with the present disclosure, there is furtherprovided a method of treatment, and a pharmaceutical composition, fortreating viral infections such as HIV infection and AIDS. The treatmentinvolves administering to a patient in need of such treatment apharmaceutical composition which contains an antiviral effective amountof one or more of the compounds of Formula I, together with one or morepharmaceutically acceptable carriers, excipients or diluents. As usedherein, the term “antiviral effective amount” means the total amount ofeach active component of the composition and method that is sufficientto show a meaningful patient benefit, i.e., inhibiting, ameliorating, orhealing of acute conditions characterized by inhibition of the HIVinfection. When applied to an individual active ingredient, administeredalone, the term refers to that ingredient alone. When applied to acombination, the term refers to combined amounts of the activeingredients that result in the therapeutic effect, whether administeredin combination, serially or simultaneously. The terms “treat, treating,treatment” as used herein and in the claims means preventing,ameliorating or healing diseases associated with HIV infection.

The pharmaceutical compositions of the invention may be in the form oforally administrable suspensions or tablets; as well as nasal sprays,sterile injectable preparations, for example, as sterile injectableaqueous or oleaginous suspensions or suppositories. Pharmaceuticallyacceptable carriers, excipients or diluents may be utilized in thepharmaceutical compositions, and are those utilized in the art ofpharmaceutical preparations.

When administered orally as a suspension, these compositions areprepared according to techniques typically known in the art ofpharmaceutical formulation and may contain microcrystalline cellulosefor imparting bulk, alginic acid or sodium alginate as a suspendingagent, methylcellulose as a viscosity enhancer, and sweeteners/flavoringagents known in the art. As immediate release tablets, thesecompositions may contain microcrystalline cellulose, dicalciumphosphate, starch, magnesium stearate and lactose and/or otherexcipients, binders, extenders, disintegrants, diluents, and lubricantsknown in the art.

The injectable solutions or suspensions may be formulated according toknown art, using suitable non-toxic, parenterally acceptable diluents orsolvents, such as mannitol, 1,3-butanediol, water, Ringer's solution orisotonic sodium chloride solution, or suitable dispersing or wetting andsuspending agents, such as sterile, bland, fixed oils, includingsynthetic mono- or diglycerides, and fatty acids, including oleic acid.

The compounds of this disclosure can be administered orally to humans ina dosage range of 1 to 100 mg/kg body weight in divided doses, usuallyover an extended period, such as days, weeks, months, or even years. Onepreferred dosage range is 1 to 10 mg/kg body weight orally in divideddoses. Another preferred dosage range is 1 to 20 mg/kg body weight individed doses. It will be understood, however, that the specific doselevel and frequency of dosage for any particular patient may be variedand will depend upon a variety of factors including the activity of thespecific compound employed, the metabolic stability and length of actionof that compound, the age, body weight, general health, sex, diet, modeand time of administration, rate of excretion, drug combination, theseverity of the particular condition, and the host undergoing therapy.

Also contemplated herein are combinations of the compounds of Formula Iherein set forth, together with one or more agents useful in thetreatment of AIDS. For example, the compounds of this disclosure may beeffectively administered, whether at periods of pre-exposure and/orpost-exposure, in combination with effective amounts of the AIDSantivirals, immunomodulators, anti-infectives, or vaccines, such asthose in the following non-limiting table:

Drug Name Manufacturer Indication ANTIVIRALS 097 Hoechst/Bayer HIVinfection, AIDS, ARC (non-nucleoside reverse transcriptase (RT)inhibitor) Amprenavir Glaxo Wellcome HIV infection, 141 W94 AIDS, ARC GW141 (protease inhibitor) Abacavir (1592U89) Glaxo Wellcome HIVinfection, GW 1592 AIDS, ARC (RT inhibitor) Acemannan Carrington LabsARC (Irving, TX) Acyclovir Burroughs Wellcome HIV infection, AIDS, ARCAD-439 Tanox Biosystems HIV infection, AIDS, ARC AD-519 Tanox BiosystemsHIV infection, AIDS, ARC Adefovir dipivoxil Gilead Sciences HIVinfection AL-721 Ethigen ARC, PGL (Los Angeles, CA) HIV positive, AIDSAlpha Interferon Glaxo Wellcome Kaposi's sarcoma, HIV in combinationw/Retrovir Ansamycin Adria Laboratories ARC LM 427 (Dublin, OH) Erbamont(Stamford, CT) Antibody which Advanced Biotherapy AIDS, ARC NeutralizespH Concepts Labile alpha aberrant (Rockville, MD) Interferon AR177Aronex Pharm HIV infection, AIDS, ARC Beta-fluoro-ddA Nat'l CancerInstitute AIDS-associated diseases BMS-234475 Bristol-Myers Squibb/ HIVinfection, (CGP-61755) Novartis AIDS, ARC (protease inhibitor) CI-1012Warner-Lambert HIV-1 infection Cidofovir Gilead Science CMV retinitis,herpes, papillomavirus Curdlan sulfate AJI Pharma USA HIV infectionCytomegalovirus MedImmune CMV retinitis Immune globin Cytovene SyntexSight threatening Ganciclovir CMV peripheral CMV retinitis DarunavirTibotec-J & J HIV infection, AIDS, ARC (protease inhibitor) DelaviridinePharmacia-Upjohn HIV infection, AIDS, ARC (RT inhibitor) Dextran SulfateUeno Fine Chem. AIDS, ARC, HIV Ind. Ltd. (Osaka, positive Japan)asymptomatic ddC Hoffman-La Roche HIV infection, AIDS, DideoxycytidineARC ddI Bristol-Myers Squibb HIV infection, AIDS, Dideoxyinosine ARC;combination with AZT/d4T DMP-450 AVID HIV infection, (Camden, NJ) AIDS,ARC (protease inhibitor) Efavirenz Bristol Myers Squibb HIV infection,(DMP 266, Sustiva ®) AIDS, ARC (−)6-Chloro-4-(S)- (non-nucleoside RTcyclopropylethynyl- inhibitor) 4(S)-trifluoro- methyl-1,4-dihydro-2H-3,1-benzoxazin- 2-one, STOCRINE EL10 Elan Corp, PLC HIV infection(Gainesville, GA) Etravirine Tibotec/J & J HIV infection, AIDS, ARC(non-nucleoside reverse transcriptase inhibitor) Famciclovir Smith Klineherpes zoster, herpes simplex GS 840 Gilead HIV infection, AIDS, ARC(reverse transcriptase inhibitor) HBY097 Hoechst Marion HIV infection,Roussel AIDS, ARC (non-nucleoside reverse transcriptase inhibitor)Hypericin VIMRx Pharm. HIV infection, AIDS, ARC Recombinant Human TritonBiosciences AIDS, Kaposi's Interferon Beta (Almeda, CA) sarcoma, ARCInterferon alfa-n3 Interferon Sciences ARC, AIDS Indinavir Merck HIVinfection, AIDS, ARC, asymptomatic HIV positive, also in combinationwith AZT/ddI/ddC ISIS 2922 ISIS Pharmaceuticals CMV retinitis KNI-272Nat'l Cancer Institute HIV-assoc. diseases Lamivudine, 3TC GlaxoWellcome HIV infection, AIDS, ARC (reverse transcriptase inhibitor);also with AZT Lobucavir Bristol-Myers Squibb CMV infection NelfinavirAgouron HIV infection, Pharmaceuticals AIDS, ARC (protease inhibitor)Nevirapine Boeheringer HIV infection, Ingleheim AIDS, ARC (RT inhibitor)Novapren Novaferon Labs, Inc. HIV inhibitor (Akron, OH) Peptide TPeninsula Labs AIDS Octapeptide (Belmont, CA) Sequence Trisodium AstraPharm. CMV retinitis, HIV Phosphonoformate Products, Inc. infection,other CMV infections PNU-140690 Pharmacia Upjohn HIV infection, AIDS,ARC (protease inhibitor) Probucol Vyrex HIV infection, AIDS RBC-CD4Sheffield Med. HIV infection, Tech (Houston, TX) AIDS, ARC RitonavirAbbott HIV infection, AIDS, ARC (protease inhibitor) SaquinavirHoffmann- HIV infection, LaRoche AIDS, ARC (protease inhibitor)Stavudine; d4T Bristol-Myers Squibb HIV infection, AIDS, Didehydrodeoxy-ARC Thymidine Tipranavir Boehringer Ingelheim HIV infection, AIDS, ARC(protease inhibitor) Valaciclovir Glaxo Wellcome Genital HSV & CMVInfections Virazole Viratek/ICN asymptomatic HIV Ribavirin (Costa Mesa,CA) positive, LAS, ARC VX-478 Vertex HIV infection, AIDS, ARCZalcitabine Hoffmann-LaRoche HIV infection, AIDS, ARC, with AZTZidovudine; AZT Glaxo Wellcome HIV infection, AIDS, ARC, Kaposi'ssarcoma, in combination with other therapies Tenofovir disoproxil,Gilead HIV infection, fumarate salt (Viread ®) AIDS, (reversetranscriptase inhibitor) Emtriva ® (Emtricitabine) Gilead HIV infection,(FTC) AIDS, (reverse transcriptase inhibitor) Combivir ® GSK HIVinfection, AIDS, (reverse transcriptase inhibitor) Abacavir succinateGSK HIV infection, (or Ziagen ®) AIDS, (reverse transcriptase inhibitor)Reyataz ® Bristol-Myers Squibb HIV infection (or atazanavir) AIDs,protease inhibitor Fuzeon ® Roche/Trimeris HIV infection (Enfuvirtide orT-20) AIDs, viral Fusion inhibitor Lexiva ® GSK/Vertex HIV infection (orFosamprenavir calcium) AIDs, viral protease inhibitor Selzentry PfizerHIV infection Maraviroc; (UK 427857) AIDs, (CCR5 antagonist, indevelopment) Trizivir ® GSK HIV infection AIDs, (three drug combination)Sch-417690 (vicriviroc) Schering-Plough HIV infection AIDs, (CCR5antagonist, in development) TAK-652 Takeda HIV infection AIDs, (CCR5antagonist, in development) GSK 873140 GSK/ONO HIV infection (ONO-4128)AIDs, (CCR5 antagonist, in development) Integrase Inhibitor Merck HIVinfection MK-0518 AIDs Raltegravir Truvada ® Gilead Combination ofTenofovir disoproxil fumarate salt (Viread ®) and Emtriva ®(Emtricitabine) Integrase Inhibitor Gilead/Japan Tobacco HIV InfectionGS917/JTK-303 AIDs Elvitegravir in development Triple drug combinationGilead/Bristol-Myers Squibb Combination of Tenofovir Atripla ®disoproxil fumarate salt (Viread ®), Emtriva ® (Emtricitabine), andSustiva ® (Efavirenz) Festinavir ® Oncolys BioPharma HIV infection AIDsin development CMX-157 Chimerix HIV infection Lipid conjugate of AIDsnucleotide tenofovir GSK1349572 GSK HIV infection Integrase inhibitorAIDs IMMUNOMODULATORS AS-101 Wyeth-Ayerst AIDS Bropirimine PharmaciaUpjohn Advanced AIDS Acemannan Carrington Labs, Inc. AIDS, ARC (Irving,TX) CL246,738 Wyeth AIDS, Kaposi's Lederle Labs sarcoma FP-21399 FukiImmunoPharm Blocks HIV fusion with CD4+ cells Gamma Interferon GenentechARC, in combination w/TNF (tumor necrosis factor) Granulocyte GeneticsInstitute AIDS Macrophage Colony Sandoz Stimulating Factor GranulocyteHoechst-Roussel AIDS Macrophage Colony Immunex Stimulating FactorGranulocyte Schering-Plough AIDS, Macrophage Colony combinationStimulating Factor w/AZT HIV Core Particle Rorer Seropositive HIVImmunostimulant IL-2 Cetus AIDS, in combination Interleukin-2 w/AZT IL-2Hoffman-LaRoche AIDS, ARC, HIV, in Interleukin-2 Immunex combinationw/AZT IL-2 Chiron AIDS, increase in Interleukin-2 CD4 cell counts(aldeslukin) Immune Globulin Cutter Biological Pediatric AIDS, inIntravenous (Berkeley, CA) combination w/AZT (human) IMREG-1 Imreg AIDS,Kaposi's (New Orleans, LA) sarcoma, ARC, PGL IMREG-2 Imreg AIDS,Kaposi's (New Orleans, LA) sarcoma, ARC, PGL Imuthiol Diethyl MerieuxInstitute AIDS, ARC Dithio Carbamate Alpha-2 Schering Plough Kaposi'ssarcoma Interferon w/AZT, AIDS Methionine- TNI Pharmaceutical AIDS, ARCEnkephalin (Chicago, IL) MTP-PE Ciba-Geigy Corp. Kaposi's sarcomaMuramyl-Tripeptide Granulocyte Amgen AIDS, in combination ColonyStimulating w/AZT Factor Remune Immune Response Immunotherapeutic Corp.rCD4 Genentech AIDS, ARC Recombinant Soluble Human CD4 rCD4-IgG AIDS,ARC hybrids Recombinant Biogen AIDS, ARC Soluble Human CD4 InterferonHoffman-La Roche Kaposi's sarcoma Alfa 2a AIDS, ARC, in combinationw/AZT SK&F106528 Smith Kline HIV infection Soluble T4 ThymopentinImmunobiology HIV infection Research Institute (Annandale, NJ) TumorNecrosis Genentech ARC, in combination Factor; TNF w/gamma InterferonANTI-INFECTIVES Clindamycin with Pharmacia Upjohn PCP PrimaquineFluconazole Pfizer Cryptococcal meningitis, candidiasis Pastille SquibbCorp. Prevention of Nystatin Pastille oral candidiasis Ornidyl MerrellDow PCP Eflornithine Pentamidine LyphoMed PCP treatment Isethionate (IM& IV) (Rosemont, IL) Trimethoprim Antibacterial Trimethoprim/sulfaAntibacterial Piritrexim Burroughs Wellcome PCP treatment PentamidineFisons Corporation PCP prophylaxis Isethionate for Inhalation SpiramycinRhone-Poulenc Cryptosporidial diarrhea Intraconazole- Janssen-Pharm.Histoplasmosis; R51211 cryptococcal meningitis TrimetrexateWarner-Lambert PCP Daunorubicin NeXstar, Sequus Kaposi's sarcomaRecombinant Human Ortho Pharm. Corp. Severe anemia Erythropoietin assoc.with AZT therapy Recombinant Human Serono AIDS-related Growth Hormonewasting, cachexia Megestrol Acetate Bristol-Myers Squibb Treatment ofanorexia assoc. W/AIDS Testosterone Alza, Smith Kline AIDS-relatedwasting Total Enteral Norwich Eaton Diarrhea and NutritionPharmaceuticals malabsorption related to AIDS

Additionally, the compounds of the disclosure herein set forth may beused in combination with other HIV entry inhibitors. Examples of suchHIV entry inhibitors are discussed in Drugs of the Future,24(12):1355-1362 (1999); Cell, 9:243-246 (Oct. 29, 1999); and DrugDiscovery Today, 5(5):183-194 (May 2000) and Meanwell, N. A. et al.,“Inhibitors of the entry of HIV into host cells”, Curr. Op. Drug Disc.Dev, 6(4):451-461 (2003). Specifically the compounds can be utilized incombination with other attachment inhibitors, fusion inhibitors, andchemokine receptor antagonists aimed at either the CCR5 or CXCR4coreceptor.

It will be understood that the scope of combinations of the compounds ofthis disclosure with AIDS antivirals, immunomodulators, anti-infectives,HIV entry inhibitors or vaccines is not limited to the list in the aboveTable but includes, in principle, any combination with anypharmaceutical composition useful for the treatment of AIDS.

Preferred combinations are simultaneous or alternating treatments with acompound of the present disclosure and an inhibitor of HIV proteaseand/or a non-nucleoside inhibitor of HIV reverse transcriptase. Anoptional fourth component in the combination is a nucleoside inhibitorof HIV reverse transcriptase, such as AZT, 3TC, ddC or ddI. A preferredinhibitor of HIV protease is REYATAZ® (active ingredient Atazanavir).Typically a dose of 300 to 600 mg is administered once a day. This maybe co-administered with a low dose of Ritonavir (50 to 500 mgs). Anotherpreferred inhibitor of HIV protease is KALETRA®. Another usefulinhibitor of HIV protease is indinavir, which is the sulfate salt ofN-(2(R)-hydroxy-1-(S)-indanyl)-2(R)-phenylmethyl-4-(S)-hydroxy-5-(1-(4-(3-pyridyl-methyl)-2(S)—N′-(t-butylcarboxamido)-piperazinyl))-pentaneamideethanolate, and is synthesized according to U.S. Pat. No. 5,413,999.Indinavir is generally administered at a dosage of 800 mg three times aday. Other preferred protease inhibitors are nelfinavir and ritonavir.Another preferred inhibitor of HIV protease is saquinavir which isadministered in a dosage of 600 or 1200 mg tid. Preferred non-nucleosideinhibitors of HIV reverse transcriptase include efavirenz. Thesecombinations may have unexpected effects on limiting the spread anddegree of infection of HIV. Preferred combinations include those withthe following (1) indinavir with efavirenz, and, optionally, AZT and/or3TC and/or ddI and/or ddC; (2) indinavir, and any of AZT and/or ddIand/or ddC and/or 3TC, in particular, indinavir and AZT and 3TC; (3)stavudine and 3TC and/or zidovudine; (4) zidovudine and lamivudine and141W94 and 1592U89; (5) zidovudine and lamivudine. (The preparation ofddC, ddI and AZT are also described in EP 0 484 071.)

In such combinations the compound of the present disclosure and otheractive agents may be administered separately or in conjunction. Inaddition, the administration of one element may be prior to, concurrentto, or subsequent to the administration of other agent(s).

General Chemistry (Methods of Synthesis)

The present invention comprises compounds of Formula I, theirpharmaceutical formulations, and their use in patients suffering from orsusceptible to HIV infection. The compounds of Formula I includepharmaceutically acceptable salts thereof. General procedures toconstruct compounds of Formula I and intermediates useful for theirsynthesis are described in the following Schemes (after theAbbreviations).

Abbreviations

One or more of the following abbreviations, most of which areconventional abbreviations well known to those skilled in the art, maybe used throughout the description of the disclosure and the examples:

h=hour(s)rt=room temperaturemol=mole(s)mmol=millimole(s)g=gram(s)mg=milligram(s)mL=milliliter(s)TFA=trifluoroacetic Acid

DCE=1,2-Dichloroethane

CH₂Cl₂=dichloromethaneTPAP=tetrapropylammonium perruthenateTHF=tetrahydrofuranDEPBT=3-(diethoxyphosphoryloxy)-1,2,3-benzotriazin-4(3H)-oneDMAP=4-dimethylaminopyridineP-EDC=polymer supported 1-(3-dimethylaminopropyl)-3-ethylcarbodiimideEDC=1-(3-dimethylaminopropyl)-3-ethylcarbodiimide

DMF=N,N-dimethylformamide Hunig's Base=N,N-diisopropylethylamine

MCPBA=meta-chloroperbenzoic acidazaindole=1H-pyrrolo-pyridine4-azaindole=1H-pyrrolo[3,2-b]pyridine5-azaindole=1H-pyrrolo[3,2-c]pyridine6-azaindole=1H-pyrrolo[2,3-c]pyridine7-azaindole=1H-pyrrolo[2,3-b]pyridinePMB=4-methoxybenzylDDQ=2,3-dichloro-5,6-dicyano-1,4-benzoquinoneOTf=trifluoromethanesulfonoxyNMM=4-methylmorpholinePIP-COPh=1-benzoylpiperazineNaHMDS=sodium hexamethyldisilazideEDAC=1-(3-dimethylaminopropyl)-3-ethylcarbodiimideTMS=trimethylsilylDCM=dichloromethaneDCE=dichloroethaneMeOH=methanolTHF=tetrahydrofuranEtOAc=ethyl acetateLDA=lithium diisopropylamideTMP-Li=2,2,6,6-tetramethylpiperidinyl lithiumDME=dimethoxyethaneDIBALH=diisobutylaluminum hydrideHOBT=1-hydroxybenzotriazoleCBZ=benzyloxycarbonylPCC=pyridinium chlorochromateTBTU=O-(benzotriazol-1-yl)—N,N,N′,N′-tetramethyluroniumtetrafluoroborateDEBPT=3-(diethoxyphosphoryloxy)-1,2,3-benzotriazin-4(3H)-oneBOP=benzotriazole-1-yl-oxy-tris-(dimethylamino)-phosphoniumhexafluorophosphate

Chemistry Intermediate ACOCOOH

The preparation of template A-CO—CO—OH has been described in detail inWO-2001062255 (T. Wang, et al.), WO-200204440 (0. Wallace, et al.) andWO-2002062423 (T. Wang, et al.).

Syntheses of the Compounds of Formula I

Detailed procedures of coupling ACOCOOH and piperazine derivative weredescribed in application (T. Wang, et al. WO-2001062255, T. Wang, et al.WO-2002062423, T. Wang, et al. US-2007249579 and T. Wang, et al.US-2004063744). ACOCOOH 1 (1 eq.), piperazine derivative 2 (1-5 eq.),3-(diethoxyphosphoryloxy)-1,2,3-benzotriazin-4(3H)-one (DEPBT) orO-(1H-benzotriazol-1-yl)—N,N,N′,N′-tetramethyluronium tetrafluoroborate(TBTU) (1-5 eq.) or(2-(7-Aza-1H-benzotriazole-1-yl)-1,1,3,3-tetramethyluroniumhexafluorophosphate) (HATU) (1-5 eq.) and Hunig's Base or N-methylmorpholine or triethyl amine (1-100 eq.) were combined in THF or DMF.The reactions were carried out at either room temperature or increasedtemperature to generate the Compounds of Formula I (Scheme 1).

Alternatively, as shown in Scheme 2, ACOCOOH 1 (1 eq.), N-Boc-piperazine3 (1-5 eq.), 3-(diethoxyphosphoryloxy)-1,2,3-benzotriazin-4(3H)-one(DEPBT) or O-(1H-benzotriazol-1-yl)—N,N,N′,N′-tetramethyluroniumtetrafluoroborate (TBTU) (1-5 eq.) or(2-(7-Aza-1H-benzotriazole-1-yl)-1,1,3,3-tetramethyluroniumhexafluorophosphate) (HATU) (1-5 eq.) and Hunig's Base or N-methylmorpholine or triethyl amine (1-100 eq.) were combined in THF or DMF.The reactions were carried out at either room temperature or increasedtemperature to offer N-Boc N′-2-ketoamide 4. The Boc protecting group ofcompound 4 was removed in a solution of TFA in dichloromethane (1% to100%) or HCl in ether (2N) at room temperature or increased temperaturefor 30 minutes to 18 hours to give free amine 5. The free amine 5coupled with acid 6 using DEPBT or TBTU or HATU as coupling agent (1-5eq.) and Hunig's Base or N-methyl morpholine or triethyl amine as basein THF or DMF at either room temperature or increased temperature toproduce the Compounds of Formula I. Or, the free amine 5 reacted withacyl chloride 7 using Hunig's Base or N-methyl morpholine or triethylamine as base in THF or DMF or CH₂Cl₂ at either room temperature orincreased temperature to produce the Compounds of Formula I.

Chemistry Experimental LC/MS Method (i.e., Compound Identification)

All Liquid Chromatography (LC) data were recorded on a Shimadzu LC-10ASor LC-20AS liquid chromotograph using a SPD-10AV or SPD-20A UV-Visdetector and Mass Spectrometry (MS) data were determined with aMicromass Platform for LC in electrospray mode.

HPLC Method (i.e., Compound Isolation)

Compounds purified by preparative HPLC were diluted in methanol (1.2 mL)and purified using a Shimadzu LC-8A or LC-10A automated preparative HPLCsystem.

Intermediate ACOCOOH

The preparation of template A-CO—CO—OH has been described in detail inWO-2001062255 (T. Wang, et al.), WO-200204440 (0. Wallace, et al.) andWO-2002062423 (T. Wang, et al.). Some examples of ACOCOOH are listed inbelow.

Intermediate 2-keto piperazine amide

Typical procedure to prepare 2-keto piperazine amide intermediates,synthesis of1-(4-methoxy-7-(3-methyl-1H-1,2,4-triazol-1-yl)-1H-pyrrolo[2,3-c]pyridin-3-yl)-2-(piperazin-1-yl)ethane-1,2-dione:

Step 1: iPr₂NEt (5 mL) was added into a solution of2-(4-methoxy-7-(3-methyl-1H-1,2,4-triazol-1-yl)-1H-pyrrolo[2,3-c]pyridin-3-yl)-2-oxoaceticacid (2 g), tert-butyl piperazine-1-carboxylate (1.24 g) and DEPBT (1.99g) in DMF (50 mL) at room temperature. The reaction was stirred for 72hours, then heated to 115° C. for 24 hours, before quenched with sodiumbicarbonate (50 mL). The aqueous layer was extracted with EtOAc (3×50ml). The combined organic phase was dried over Mg₂SO₄ and concentratedunder vacuum to give a crude product, which was partially purified byHPLC, while the rest was used in the further step without purification.

MS (M − H)⁺ Calcd. 468.2 MS (M − H)⁺ Observ. 468.3 Retention Time 1.40min LC Condition Solvent A 5% ACN: 95% Water: 10 mM Ammonium ActetateSolvent B 95% ACN: 5% Water: 10 mM Ammonium Actetate Start % B  0 Final% B 100 Gradient Time 2 min Flow Rate 4 mL/min Wavelength 220 SolventPair ACN: Water: Ammonium Actetate Column PHENOMENEX-LUNA, 4.6 × 50 mm,S5

Step 2: TFA (4 mL) was added into a solution of tert-butyl4-(2-(4-methoxy-7-(3-methyl-1H-1,2,4-triazol-1-yl)-1H-pyrrolo[2,3-c]pyridin-3-yl)-2-oxoacetyl)piperazine-1-carboxylate(500 mg) in CH₂Cl₂ (20 mL) at room temperature. The reaction was stirredovernight and quenched with sodium bicarbonate (20 mL). The aqueouslayer was extracted with EtOAc (3×20 mL). The combined organic phase wasdried over Mg₂SO₄ and concentrated under vacuum to give a crude product,which was purified by silica gel chromatography.

MS (M + H)⁺ Calcd. 370.2 MS (M + H)⁺ Observ. 370.2 Retention Time 0.90min LC Condition Solvent A 5% ACN: 95% Water: 10 mM Ammonium ActetateSolvent B 95% ACN: 5% Water: 10 mM Ammonium Actetate Start % B  0 Final% B 100 Gradient Time 2 min Flow Rate 4 mL/min Wavelength 220 SolventPair ACN: Water: Ammonium Actetate Column PHENOMENEX-LUNA, 4.6 × 50 mm,S5

1-(4-Fluoro-7-(1H-1,2,3-triazol-1-yl)-1H-pyrrolo[2,3-c]pyridin-3-yl)-2-(piperazin-1-yl)ethane-1,2-dionewas synthesis via the same process to prepare1-(4-methoxy-7-(3-methyl-1H-1,2,4-triazol-1-yl)-1H-pyrrolo[2,3-c]pyridin-3-yl)-2-(piperazin-1-yl)ethane-1,2-dione,using2-(4-fluoro-7-(1H-1,2,3-triazol-1-yl)-1H-pyrrolo[2,3-c]pyridin-3-yl)-2-oxoaceticacid as a starting material.

MS (M + H)⁺ Calcd. 344.1 MS (M + H)⁺ Observ. 344.2 Retention Time 0.95min LC Condition Solvent A 5% ACN: 95% Water: 10 mM Ammonium ActetateSolvent B 95% ACN: 5% Water: 10 mM Ammonium Actetate Start % B  0 Final% B 100 Gradient Time 2 min Flow Rate 4 mL/min Wavelength 220 SolventPair ACN: Water: Ammonium Actetate Column PHENOMENEX-LUNA, 4.6 × 50 mm,S5

1-(4-Methoxy-7-(1H-1,2,3-triazol-1-yl)-1H-pyrrolo[2,3-c]pyridin-3-yl)-2-(piperazin-1-yl)ethane-1,2-dionewas synthesis via the same process to prepare1-(4-methoxy-7-(3-methyl-1H-1,2,4-triazol-1-yl)-1H-pyrrolo[2,3-c]pyridin-3-yl)-2-(piperazin-1-yl)ethane-1,2-dione,using2-(4-methoxy-7-(1H-1,2,3-triazol-1-yl)-1H-pyrrolo[2,3-c]pyridin-3-yl)-2-oxoaceticacid as a starting material.

  1-(4-methoxy-7-(1H-1,2,3-triazol-1-yl)-1H-pyrrolo[2,3-c]pyridin-3-yl)-2- (piperazin-1-yl)ethane-1,2-dione MS (M +H)⁺ Calcd. 356.1 MS (M + H)⁺ Observ. 356.0 Retention Time 0.98 min LCCondition Solvent A 90% Water-10% Methanol-0.1% TFA Solvent B 10%Water-90% Methanol-0.1% TFA Start % B  0   Final % B 100   Gradient Time2 min Flow Rate 5 mL/min Wavelength 220   Solvent PairWater-Methanol-TFA Column Xterra 4.6 × 50 mm C18 5 um

Syntheses of the Compounds of Formula I Preparation of Compound 1001,1-(4-fluoro-7-(1H-1,2,3-triazol-1-yl)-1H-pyrrolo[2,3-c]pyridin-3-yl)-2-(4-(3-methylbutanoyl)piperazin-1-yl)ethane-1,2-dione

2-(4-Fluoro-7-(1H-1,2,3-triazol-1-yl)-1H-pyrrolo[2,3-c]pyridin-3-yl)-2-oxoaceticacid (100 mg), 3-methyl-1-(piperazin-1-yl)butan-1-one (74 mg), TBTU (128mg) and Hunig's Base (0.2 mL) were combined in DMF (1.5 mL). The mixturewas stirred at room temperature for 17 hours. DMF was removed viaevaporation at reduced pressure and the residue was recrystallized inMeOH to give Compound 1001 (54 mg).

  1001 MS (M + H)⁺ Calcd. 428.2 MS (M + H)⁺ Observ. 427.9 Retention Time1.73 min LC Condition Solvent A 90% Water-10% Methanol-0.1% TFA SolventB 10% Water-90% Methanol-0.1% TFA Start % B  0   Final % B 100  Gradient Time 2 min Flow Rate 4 mL/min Wavelength 220   Solvent PairWater-Methanol-TFA Column PHENOMENEX-LUNA 4.6 × 50 mm S10

Preparation of Compound 1002,1-(4-(cyclohexanecarbonyl)piperazin-1-yl)-2-(4-methoxy-7-(1H-1,2,3-triazol-1-yl)-1H-pyrrolo[2,3-c]pyridin-3-yl)ethane-1,2-dioneand Compound 1003

1-(4-Methoxy-7-(1H-1,2,3-triazol-1-yl)-1H-pyrrolo[2,3-c]pyridin-3-yl)-2-(piperazin-1-yl)ethane-1,2-dione(100 mg) and cyclohexanecarbonyl chloride (41 mg) were combined in 10%Et₃N in THF (5 mL). The mixture was stirred at room temperature for 3hour, before was quenched by 5 mL of saturated NaHCO₃ aqueous solution.The aqueous phase was extracted with EtOAc (2×10 mL). The combinedorganic layer was combined, washed with brine (30 mL), dried over MgSO₄and concentrated under vacuum to give a residue which was purified bypreparative HPLC to afford Compound 1002 (30 mg).

  1002 MS (M + H)⁺ Calcd. 466.2 MS (M + H)⁺ Observ. 466.1 Retention Time2.20 min LC Condition Solvent A 90% Water-10% Methanol-0.1% TFA SolventB 10% Water-90% Methanol-0.1% TFA Start % B  0   Final % B 100  Gradient Time 2 min Flow Rate 5 mL/min Wavelength 220   Solvent PairWater-Methanol-TFA Column XTERRA 4.6 × 30 mm S5

Compound 1003 was synthesis via the same process to prepare Compound1002, using 1-adamantanecabonyl chloride as a starting material.

  1003 MS (M + H)⁺ Calcd. 518.2 MS (M + H)⁺ Observ. 518.2 Retention Time2.43 min LC Condition Solvent A 90% Water-10% Methanol-0.1% TFA SolventB 10% Water-90% Methanol-0.1% TFA Start % B  0   Final % B 100  Gradient Time 2 min Flow Rate 5 mL/min Wavelength 220   Solvent PairWater-Methanol-TFA Column XTERRA 4.6 × 30 mm S5

Preparation of Compound 1004,1-(4-(cycloheptanecarbonyl)piperazin-1-yl)-2-(4-methoxy-7-(1H-1,2,3-triazol-1-yl)-1H-pyrrolo[2,3-c]pyridin-3-yl)ethane-1,2-dione

1-(4-Methoxy-7-(1H-1,2,3-triazol-1-yl)-1H-pyrrolo[2,3-c]pyridin-3-yl)-2-(piperazin-1-yl)ethane-1,2-dione(50 mg), cycloheptanecarboxylic acid (26 mg), TBTU (64 mg) and Hunig'sBase (0.1 mL) were combined in DMF (1 mL). The mixture was stirred atroom temperature for 24 hours, before was quenched by 5 mL of saturatedNaHCO₃ aqueous solution. The aqueous phase was extracted with EtOAc(2×10 mL). The combined organic layer was combined, washed with brine(30 mL), dried over MgSO₄ and concentrated under vacuum to give aresidue which was purified by preparative HPLC to afford Compound 1004(10 mg).

  1004 MS (M + H)⁺ Calcd. 480.2 MS (M + H)⁺ Observ. 480.2 Retention Time1.73 min LC Condition Solvent A 90% Water-10% Methanol-0.1% TFA SolventB 10% Water-90% Methanol-0.1% TFA Start % B  0   Final % B 100  Gradient Time 2 min Flow Rate 4 mL/min Wavelength 220   Solvent PairWater-Methanol-TFA Column PHENOMENEX-LUNA 4.6 × 50 mm S10

The following methods were used to prepare Compounds 2001-2051.

Analytical HPLC method 1: Waters Xbridge 2.1×50 mm 5 um C18, A=5:95ACN:Water; B=95:5 ACN:Water; Modifier=10 mM NH₄OAc. 0.00 min=0% B, 2.0min=100% B, 3.0 min=100% B, 3.05 min=0% B, 3.5 min=0% B, Flow rate=1mL/min

Analytical HPLC method 2: Phenomenex, Gemini 100×4.6 mm, 5u C18,A=Water, B=ACN; Modifier=10 mM NH₄OAc. 0.00 min=10% B, 6.0 min=95% B,6.5 min=95% B, 7.0 min=10% B, 8.0 min=10% B, Flow rate=1.2 mL/min

Analytical HPLC method 3: Onyx Monolithic C18 50×4.6 mm, 5u C18,A=Water, B=ACN; Modifier=10 mM NH₄OAc. 0.00 min=10% B, 3.0 min=95% B,4.0 min=95% B, 4.2 min=10% B, 5.0 min=10% B, Flow rate=1.2 mL/min

The general procedures below pertain to the experimental procedure forlibrary compounds.

1-(4-Fluoro-7-(1H-1,2,3-triazol-1-yl)-1H-pyrrolo[2,3-c]pyridin-3-yl)-2-(piperazin-1-yl)ethane-1,2-dionehydrochloride (1 eq.) in DMF was added into a Wheaton tube (16×100 mm)which contained pre-weighed acid (3 eq.) and followed by adding DIPEA (5eq.) and DMF. The mixture was shaken at room temperature overnight. Allsamples were transferred into a plate and purified by HPLC.

1-(4-Methoxy-7-(3-methyl-1H-1,2,4-triazol-1-yl)-1H-pyrrolo[2,3-c]pyridin-3-yl)-2-(piperazin-1-yl)ethane-1,2-dione(1 eq.) in DMF was added into a Wheaton tube (16×100 mm) which containedpre-weighed acid (3 eq.) and followed by adding DIPEA (5 eq.) and DMF.The mixture was shaken at room temperature overnight. All samples weretransferred into a plate and purified by HPLC.

MS MS (M + H)⁺ (M + H)⁺ RT Cmpd # Structure Calcd. Observ. (min) Method2001

468.2 468.2 7.09 1 2002

442.2 442.2 4.12 1 2003

468.2 468.3 6.92 1 2004

492.2 492.2 7.36 1 2005

468.2 468.3 6.93 1 2006

469.2 469.2 3.36 1 2007

455.2 455.2 3.05 1 2008

496.2 496.2 4.89 1 2009

510.3 510.3 8.86 1 2010

496.2 496.2 4.22 1 2011

494.2 494.2 7.99 1 2012

468.2 468.3 7.08 1 2013

455.2 455.2 3.94 1 2014

456.2 456.2 4.06 1 2015

442.2 442.2 3.95 1 2016

506.2 506.3 8.12 1 2017

454.2 454.2 6.32 1 2018

470.2 470.2 3.97 1 2019

478.2 478.0 3.455 2 2020

469.2 469.1 2.351 2 2021

469.2 469.0 2.397 2 2022

490.2 490.0 3.888 2 2023

478.2 478.0 3.451 2 2024

456.2 456.0 3.088 2 2025

511.3 511.2 2.547 2 2026

577.2 577.2 4.58 2 2027

550.3 550.2 3.792 2 2028

483.2 483.1 2.805 2 2029

469.2 469.1 2.547 2 2030

455.2 455.0 2.38 2 2031

577.2 577.2 4.572 2 2032

549.3 549.2 2.98 2 2033

541.2 541.2 3.93 2 2034

555.3 555.2 4.126 2 2035

555.3 555.2 4.022 2 2036

505.2 505.1 3.163 2 2037

505.2 505.1 3.159 2 2038

412.2 412.0 1.05 3 2039

414.2 414.1 1.17 3 2040

468.2 468.2 1.61 1 2041

494.3 494.3 1.7 1 2042

442.2 442.2 1.58 1 2043

468.2 468.2 1.66 1 2044

416.2 416.2 1.26 1 2045

429.2 429.2 1.13 1 2046

400.2 400.2 1.29 1 2047

460.2 460.2 1.27 1 2048

442.2 442.3 4.015 1 2049

455.2 455.3 3.868 1 2050

426.2 426.3 4.437 1 2051

486.2 486.3 4.213 1

Biology Data for the Examples

“μM” means micromolar;

“mL” means milliliter;

“μl” means microliter;

“mg” means milligram;

The materials and experimental procedures used to obtain the resultsreported in Table 2 are described below.

Cells:

-   -   Virus production—Human embryonic Kidney cell line, 293T (HEK        293T), was propagated in Dulbecco's Modified Eagle Medium        (Invitrogen, Carlsbad, Calif.) containing 10% fetal Bovine serum        (FBS, Sigma, St. Louis, Mo.). The human T-cell leukemia cell MT2        (AIDS Research and Reference Reagent Program, Cat. 237) was        propagated in RPMI 1640 (Invitrogen, Carlsbad, Calif.)        containing 10% fetal bovine serum (FBS, Hyclone, Logan, Utah)    -   Virus infection—Single-round infectious reporter virus was        produced by co-transfecting HEK 293T cells with plasmide        expressing the HIV-1 LAI envelope along with a plasmid        containing an HIV-1 LAI proviral cDNA with the envelope gene        replaced by a firefly luciferase reporter gene (Chen et al, Ref        41). Transfections were performed using lipofectAMINE PLUS        reagent as described by the manufacturer (Invitrogen, Carlsbad,        Calif.).

Experimental Procedure

-   1. MT2 cells were plated in black, 384 well plates at a cell density    of 5×10³ cells per well in 25 μl RPMI 1640 containing 10% FBS.-   2. Compound (diluted in dimethylsulfoxide and growth medium) was    added to cells at 12.5 μl/well, so that the final assay    concentration would be <50 nM.-   3. 12.5 μl of single-round infectious reporter virus in Dulbecco's    Modified Eagle Medium was added to the plated cells and compound at    an approximate multiplicity of infection (MOI) of 0.01, resulting in    a final volume of 50 μl per well.-   4. Virus-infected cells were incubated at 37 degrees Celsius, in a    CO₂ incubator, and harvested 72 h after infection.-   5. Viral infection was monitored by measuring luciferase expression    in the infected cells using a luciferase reporter gene assay kit    (Steady-Glo, Promega, Madison, Wis.) as described by the    manufacturer. Luciferase activity was then quantified by measuring    luminescence using an EnVision Multilabel Plate Readers    (PerkinElmer, Waltham, Mass.).-   6. The percent inhibition for each compound was calculated by    quantifying the level of luciferase expression in cells infected in    the presence of each compound as a percentage of that observed for    cells infected in the absence of compound and subtracting such a    determined value from 100.-   7. An EC₅₀ provides a method for comparing the antiviral potency of    the compounds of this disclosure. The effective concentration for    fifty percent inhibition (EC₅₀) was calculated with the Microsoft    Excel Xlfit curve fitting software. For each compound, curves were    generated from percent inhibition calculated at 10 different    concentrations by using a four paramenter logistic model (model    205). The EC₅₀ data for the compounds is shown in Table 2. Table 1    is the key for the data in Table 2.

TABLE 1 Biological Data Key for EC₅₀s Compounds with Compounds withEC₅₀s >0.5 μM EC₅₀ <0.5 μM Group B Group A

TABLE 2 Compd. EC₅₀ Number Structure Group from Table 1 1001

A 1002

A 1003

A 1004

A 0.14 nM 2001

A 2002

A 2003

A 2004

A 1.15 nM 2005

A 0.36 nM 2006

B 2007

B 2008

A 5.1 nM 2009

B 2010

A 2011

B 2012

A 2013

A 450.6 nM 2014

A 12.5 nM 2015

A 2016

A 2017

A 0.11 nM 2018

A 2019

A 344.4 nM 2020

B 2021

A 76.9 nM 2022

A 2023

A 2024

A 2025

B 2026

B 2027

A 2028

A 25.5 nM 2029

B 2030

B 2031

B 2032

B 2033

B 2034

B 2035

B 2036

B 2037

B 2038

A 2039

A 2040

A 2041

A 2042

A 2043

A 2044

A 2045

B 2046

A 6.88 nM 2047

B 2048

A 2049

B 2050

A 10.4 nM 2051

B

The foregoing description is merely illustrative and should not beunderstood to limit the scope or underlying principles of the inventionin any way. Indeed, various modifications of the invention, in additionto those shown and described herein, will become apparent to thoseskilled in the art from the following examples and the foregoingdescription. Such modifications are also intended to fall within thescope of the appended claims.

What is claimed is:
 1. A compound of Formula I, includingpharmaceutically acceptable salts thereof:

wherein A is selected from the group consisting of:

wherein a, b, c, d and e are independently selected from the groupconsisting of hydrogen, halogen, cyano, nitro, COOR⁵⁶, XR⁵⁷, NA¹A²,C(O)R⁷, C(O)NR⁵⁵R⁵⁶, B, Q, and E; B is selected from the groupconsisting of —C(═NR⁴⁶)(R⁴⁷), C(O)NR⁴⁰R⁴¹, aryl, heteroaryl,heteroalicyclic, S(O)₂R⁸, C(O)R⁷, XR^(8a), (C₁₋₆)alkylNR⁴⁰R⁴¹,(C₁₋₆)alkylCOOR^(8b); wherein said aryl, heteroaryl, and heteroalicyclicare optionally substituted with one to three same or different halogensor from one to three same or different substituents selected from thegroup F; wherein aryl is napthyl or substituted phenyl; whereinheteroaryl is a mono or bicyclic system which contains from 3 to 7 ringatoms for a mono cyclic system and up to 12 atoms in a fused bicyclicsystem, including from 1 to 4 heteroatoms; wherein heteroalicyclic is a3 to 7 membered mono cyclic ring which may contain from 1 to 2heteroatoms in the ring skeleton and which may be fused to a benzene orpyridine ring; Q is selected from the group consisting of (C₁₋₆)alkyland (C₂₋₆)alkenyl; wherein said (C₁₋₆)alkyl and (C₂₋₆)alkenyl areoptionally substituted with one to three same or different halogens orfrom one to three same or different substituents selected from the groupconsisting of C(O)NR⁵⁵R⁵⁶, hydroxy, cyano and XR⁵⁷; E is selected fromthe group consisting of (C₁₋₆)alkyl and (C₂₋₆)alkenyl; wherein said(C₁₋₆)alkyl and (C₂₋₆)alkenyl are independently optionally substitutedwith a member selected from the group consisting of phenyl, heteroaryl,SMe, SPh, —C(O)NR⁵⁶R⁵⁷, C(O)R⁵⁷, SO₂(C₁₋₆)alkyl and SO₂Ph; whereinheteroaryl is a monocyclic system which contains from 3 to 7 ring atoms,including from 1 to 4 heteroatoms; R⁷ is selected from the groupconsisting of aryl, heteroaryl, and heteroalicyclic; wherein said aryl,heteroaryl, and heteroalicyclic are optionally substituted with one tothree same or different halogens or with from one to three same ordifferent substituents selected from the group F; wherein for R⁷, R⁸,R^(8a), R^(8b) aryl is phenyl; heteroaryl is a mono or bicyclic systemwhich contains from 3 to 7 ring atoms for mono cyclic systems and up to10 atoms in a bicyclic system, including from 1 to 4 heteroatoms;wherein heteroalicyclic is selected from the group consisting ofaziridine, azetidine, pyrrolidine, piperazine, piperidine,tetrahydrofuran, tetrahydropyran, azepine, and morpholine; F is selectedfrom the group consisting of (C₁₋₆)alkyl, (C₃₋₇)cycloalkyl, aryl,heteroaryl, heteroalicyclic, hydroxy, (C₁₋₆)alkoxy, aryloxy,(C₁₋₆)thioalkoxy, cyano, halogen, nitro, —C(O)R⁵⁷, benzyl,—NR⁴²C(O)—(C₁₋₆)alkyl, —NR⁴²C(O)—(C₃₋₆)cycloalkyl, —NR⁴²C(O)-aryl,—NR⁴²C(O)-heteroaryl, —NR⁴²C(O)-heteroalicyclic, a 4, 5, or 6 memberedring cyclic N-lactam, —NR⁴²S(O)₂—(C₁₋₆)alkyl,—NR⁴²S(O)₂—(C₃₋₆)cycloalkyl, —NR⁴²S(O)2-aryl, —NR⁴²S(O)₂-heteroaryl,—NR⁴²S(O)₂-heteroalicyclic, S(O)₂(C₁₋₆)alkyl, S(O)₂aryl, —S(O)2 NR⁴²R⁴³,NR⁴²R⁴³, (C₁₋₆)alkylC(O)NR⁴²R⁴³, C(O)NR⁴²R⁴³, NHC(O)NR⁴²R⁴³,OC(O)NR⁴²R⁴³, NHC(O)OR⁵⁴, (C₁₋₆)alkylNR⁴²R⁴³, COOR⁵⁴, and(C₁₋₆)alkylCOOR⁵⁴; wherein said (C₁₋₆)alkyl, (C₃₋₇)cycloalkyl, aryl,heteroaryl, heteroalicyclic, (C₁₋₆)alkoxy, and aryloxy, are optionallysubstituted with one to nine same or different halogens or from one tofive same or different substituents selected from the group G; whereinaryl is phenyl; heteroaryl is a monocyclic system which contains from 3to 7 ring atoms, including from 1 to 4 heteroatoms; heteroalicyclic isselected from the group consisting of aziridine, azetidine, pyrrolidine,piperazine, piperidine, tetrahydrofuran, tetrahydropyran, azepine, andmorpholine; R⁸ is selected from the group consisting of hydrogen,(C₁₋₆)alkyl, (C₃₋₇)cycloalkyl, (C₂₋₆)alkenyl, (C₃₋₇)cycloalkenyl,(C₂₋₆)alkynyl, aryl, heteroaryl, and heteroalicyclic; wherein said(C₁₋₆)alkyl, (C₃₋₇)cycloalkyl, (C₂₋₆)alkenyl, (C₃₋₇)cycloalkenyl,(C₂₋₆)alkynyl, aryl, heteroaryl, and heteroalicyclic are optionallysubstituted with one to six same or different halogens or from one tofive same or different substituents selected from the group F or(C₁₋₆)alkyl, (C₃₋₆)cycloalkyl, cyano, phenyl, aryl, heteroaryl,heteroalicyclic, hydroxy, (C₁₋₆)alkoxy, halogen, benzyl, primary amine,secondary amine, tertiary amine, ammonium, nitro, thiol, thioether,alcohol, ether, acid, aldehyde, ketone, amide, amidine, guanidine,sulfone, sulfonamide, sulfamide, acyl sulfamide, sulfate, sulfuric acid,sulfamic acid, phosphate, phosphoric acid, boronic ester, boronic acid,squarate, squaric acid, oxime, hydrazine, peroxide, among which ether,peroxide, thioether, secondary amine, tertiary amine, ammonium, ester,ketone, amide, amidine, oxime, hydrazine can be either acyclic orcyclic; heteroaryl is selected from the group consisting of furanyl,thienyl, thiazolyl, isothiazolyl, oxazolyl, isoxazolyl, imidazolyl,oxadiazolyl, thiadiazolyl, pyrazolyl, tetrazolyl, triazolyl, pyridinyl,pyrazinyl, pyridazinyl, and pyrimidinyl; R^(8a) is a member selectedfrom the group consisting of aryl, heteroaryl, and heteroalicyclic;wherein each member is independently optionally substituted with one tosix same or different halogens or from one to five same or differentsubstituents selected from the group F; R^(8b) is selected from thegroup consisting of hydrogen, (C₁₋₆)alkyl and phenyl; X is selected fromthe group consisting of NH or NCH₃, O, and S; R⁴⁰ and R⁴¹ areindependently selected from the group consisting of (a) hydrogen; (b)(C₁₋₆)alkyl or (C₃₋₇)cycloalkyl substituted with one to three same ordifferent halogens or from one to two same or different substituentsselected from the group F or different functional groups: (C₁₋₆)alkyl,(C₃₋₆)cycloalkyl, cyano, phenyl, aryl, heteroaryl, heteroalicyclic,hydroxy, (C₁₋₆)alkoxy, halogen, benzyl, primary amine, secondary amine,tertiary amine, ammonium, nitro, thiol, thioether, alcohol, ether, acid,aldehyde, ketone, amide, amidine, guanidine, sulfone, sulfonamide,sulfamide, acyl sulfamide, sulfate, sulfuric acid, sulfamic acid,phosphate, phosphoric acid, boronic ester, boronic acid, squarate,squaric acid, oxime, hydrazine, peroxide, among which ether, peroxide,thioether, secondary amine, tertiary amine, ammonium, ester, ketone,amide, amidine, oxime, hydrazine can be either acyclic or cyclic;heteroaryl is selected from the group consisting of furanyl, thienyl,thiazolyl, isothiazolyl, oxazolyl, isoxazolyl, imidazolyl, oxadiazolyl,thiadiazolyl, pyrazolyl, tetrazolyl, triazolyl, pyridinyl, pyrazinyl,pyridazinyl, and pyrimidinyl; and (c) (C₁₋₆)alkoxy, aryl, heteroaryl orheteroalicyclic; or R⁴⁰ and R⁴¹ taken together with the nitrogen towhich they are attached form a member selected from the group consistingof aziridine, azetidine, pyrrolidine, piperazine, 4—NMe piperazine,piperidine, azepine, and morpholine; and wherein said aryl, heteroaryl,and heteroalicyclic are optionally substituted with one to three same ordifferent halogens or from one to two same or different substituentsselected from the group F; wherein for R⁴⁰ and R⁴¹ aryl is phenyl;heteroaryl is a monocyclic system which contains from 3 to 6 ring atoms,including from 1 to 4 heteroatoms; heteroalicyclic is selected from thegroup consisting of aziridine, azetidine, pyrrolidine, piperazine,piperidine, tetrahydrofuran, tetrahydropyran, azepine, and morpholine;provided when B is C(O)NR⁴⁰R⁴¹, at least one of R⁴⁰ and R⁴¹ is notselected from groups (a) or (b); R⁴² and R⁴³ are independently selectedfrom the group consisting of hydrogen, (C₁₋₆)alkyl, allyl, (C₁₋₆)alkoxy,(C₃₋₇)cycloalkyl, aryl, heteroaryl and heteroalicyclic; or R⁴² and R⁴³taken together with the nitrogen to which they are attached form amember selected from the group consisting of aziridine, azetidine,pyrrolidine, piperazine, 4—NMe piperazine, piperidine, azepine, andmorpholine; and wherein said (C₁₋₆)alkyl, (C₁₋₆)alkoxy,(C₃₋₇)cycloalkyl, aryl, heteroaryl, and heteroalicyclic are optionallysubstituted with one to three same or different halogens or from one totwo same or different substituents selected from the group G ordifferent functional groups: (C₁₋₆)alkyl, (C₃₋₆)cycloalkyl, cyano,phenyl, aryl, heteroaryl, heteroalicyclic, hydroxy, (C₁₋₆)alkoxy,halogen, benzyl, primary amine, secondary amine, tertiary amine,ammonium, nitro, thiol, thioether, alcohol, ether, acid, aldehyde,ketone, amide, amidine, guanidine, sulfone, sulfonamide, sulfamide, acylsulfamide, sulfate, sulfuric acid, sulfamic acid, phosphate, phosphoricacid, boronic ester, boronic acid, squarate, squaric acid, oxime,hydrazine, peroxide, among which ether, peroxide, thioether, secondaryamine, tertiary amine, ammonium, ester, ketone, amide, amidine, oxime,hydrazine can be either acyclic or cyclic; heteroaryl is selected fromthe group consisting of furanyl, thienyl, thiazolyl, isothiazolyl,oxazolyl, isoxazolyl, imidazolyl, oxadiazolyl, thiadiazolyl, pyrazolyl,tetrazolyl, triazolyl, pyridinyl, pyrazinyl, pyridazinyl, andpyrimidinyl; wherein for R⁴² and R⁴³ aryl is phenyl; heteroaryl is amonocyclic system which contains from 3 to 6 ring atoms, including from1 to 4 heteroatoms; heteroalicyclic is a member selected from the groupconsisting of aziridine, azetidine, pyrrolidine, piperazine, piperidine,tetrahydrofuran, tetrahydropyran, azepine, and morpholine; G is selectedfrom the group consisting of (C₁₋₆)alkyl, (C₃₋₇)cycloalkyl, aryl,heteroaryl, heteroalicyclic, hydroxy, (C₁₋₆)alkoxy, aryloxy, cyano,halogen, nitro, —C(O)R⁵⁷, benzyl, —NR⁴⁸C(O)—(C₁₋₆)alkyl,—NR⁴⁸C(O)—(C₃₋₆)cycloalkyl, —NR⁴⁸C(O)-aryl, —NR⁴⁸C(O)-heteroaryl,—NR⁴⁸C(O)-heteroalicyclic, a 4, 5, or 6 membered ring cyclic N-lactam,—NR⁴⁸S(O)₂—(C₁₋₆)alkyl, —NR⁴⁸S(O)₂—(C₃₋₆)cycloalkyl, —NR⁴⁸S(O)2-aryl,—NR⁴⁸S(O)₂-heteroaryl, —NR⁴⁸S(O)2-heteroalicyclic, sulfinyl, sulfonyl,sulfonamide, NR⁴⁸R⁴⁹, (C₁₋₆)alkyl C(O)NR⁴⁸R⁴⁹, C(O)NR⁴⁸R⁴⁹,NHC(O)NR⁴⁸R⁴⁹, OC(O)NR⁴⁸R⁴⁹, NHC(O)OR^(54′), (C₁₋₆)alkylNR⁴⁸R⁴⁹, COOR⁵⁴,and (C₁₋₆)alkylCOOR⁵⁴; wherein aryl is phenyl; heteroaryl is amonocyclic system which contains from 3 to 7 ring atoms, including from1 to 4 heteroatoms; heteroalicyclic is selected from the groupconsisting of aziridine, azetidine, pyrrolidine, piperazine, piperidine,tetrahydrofuran, tetrahydropyran, azepine, and morpholine; R⁴⁶ isselected from the group consisting of H, OR⁵⁷, and NR⁵⁵R⁵⁶; R⁴⁷ isselected from the group consisting of H, amino, halogen, phenyl, aryl,heteroaryl and (C₁₋₆)alkyl; R⁴⁸ and R⁴⁹ are independently selected fromthe group consisting of hydrogen, (C₁₋₆)alkyl, phenyl, aryl andheteroaryl; R⁵⁰ is selected from the group consisting of H, (C₁₋₆)alkyl,(C₃₋₆)cycloalkyl, and benzyl; wherein each of said (C₁₋₆)alkyl,(C₃₋₇)cycloalkyl and benzyl are optionally substituted with one to threesame or different (C₁₋₆)alkyl, (C₃₋₆)cycloalkyl, cyano, phenyl, aryl,heteroaryl, heteroalicyclic, hydroxy, (C₁₋₆)alkoxy, halogen, benzyl,primary amine, secondary amine, tertiary amine, ammonium, nitro, thiol,thioether, alcohol, ether, acid, aldehyde, ketone, amide, amidine,guanidine, sulfone, sulfonamide, sulfamide, acyl sulfamide, sulfate,sulfuric acid, sulfamic acid, phosphate, phosphoric acid, boronic ester,boronic acid, squarate, squaric acid, oxime, hydrazine, peroxide, amongwhich ether, peroxide, thioether, secondary amine, tertiary amine,ammonium, ester, ketone, amide, amidine, oxime, hydrazine can be eitheracyclic or cyclic; heteroaryl is selected from the group consisting offuranyl, thienyl, thiazolyl, isothiazolyl, oxazolyl, isoxazolyl,imidazolyl, oxadiazolyl, thiadiazolyl, pyrazolyl, tetrazolyl, triazolyl,pyridinyl, pyrazinyl, pyridazinyl, and pyrimidinyl R⁵⁴ is selected fromthe group consisting of hydrogen and (C₁₋₆)alkyl; R^(54′) is(C₁₋₆)alkyl; R⁵⁵ and R⁵⁶ are independently selected from the groupconsisting of hydrogen and (C₁₋₆)alkyl; and R⁵⁷ is selected from thegroup consisting of hydrogen, (C₁₋₆)alkyl, aryl, heteroaryl; and A¹ andA² are independently selected from hydrogen, (C₁₋₆)alkyl, aryl,heteroaryl, SO2D¹, SO2ND²D³, COD⁴, COCOD⁴, COOD⁴, COND⁵D⁶, COCOND⁵D⁶,COCOOD⁴, C(═ND⁷)D⁸, C(═ND⁹)ND¹⁰D¹¹; A¹ and A² can either never connectwith each other, or conjoin to form a ring structure; D¹, D², D³, D⁴,D⁵, D⁶, D⁷, D⁸, D⁹, D¹⁰, and D¹¹ are each independently selected fromthe group consisting of H, C₁-C₅₀ alkyl, C₃-C₅₀ cycloalkyl, C₃-C₅₀alkenyl, C₄-C₅₀ cycloalkenyl, phenyl, heteroaryl, C₃-C₅₀ amide andC₃-C₅₀ ether; heteroaryl is selected from the group consisting ofpyridinyl, pyrazinyl, pyridazinyl, pyrimidinyl, furanyl, thienyl,benzothienyl, thiazolyl, isothiazolyl, oxazolyl, benzooxazolyl,isoxazolyl, imidazolyl, benzoimidazolyl, 1H-imidazo[4,5-b]pyridin-2-yl,1H-imidazo[4,5-c]pyridin-2-yl, oxadiazolyl, thiadiazolyl, pyrazolyl,tetrazolyl, tetrazinyl, triazinyl and triazolyl; provided the carbonatoms which comprise the carbon-carbon double bond of said C₃-C₂₀alkenyl or the carbon-carbon triple bond of said C₃-C₂₀ alkynyl are notthe point of attachment to the nitrogen to which D², D³, D⁵, D⁶, D⁷, D⁹,D¹⁰, and D¹¹ is attached; wherein said C₁-C₅₀ alkyl, C₃-C₅₀ cycloalkyl,C₃-C₅₀ alkenyl, C₄-C₅₀ cycloalkenyl, aryl, phenyl, heteroaryl, C₃-C₅₀amide and C₃-C₅₀ ether is optionally substituted with one to three sameor different of the following functionalities: (C₁₋₆)alkyl,(C₃₋₆)cycloalkyl, cyano, phenyl, aryl, heteroaryl, heteroalicyclic,hydroxy, (C₁₋₆)alkoxy, halogen, benzyl, primary amine, secondary amine,tertiary amine, ammonium, nitro, thiol, thioether, alcohol, ether, acid,aldehyde, ketone, amide, amidine, guanidine, sulfone, sulfonamide,sulfamide, acyl sulfamide, sulfate, sulfuric acid, sulfamic acid,phosphate, phosphoric acid, boronic ester, boronic acid, squarate,squaric acid, oxime, hydrazine, peroxide, among which ether, peroxide,thioether, secondary amine, tertiary amine, ammonium, ester, ketone,amide, amidine, oxime, hydrazine can be either acyclic or cyclic; I₁,I₂, I₃, I₄, I₅, I₆, I₇ and I₈ are each independently selected from thegroup consisting of H, (C₁₋₆)alkyl, (C₃₋₆) cycloalkyl, (C₂₋₆) alkenyl,(C₄₋₆) cycloalkenyl, (C₂₋₆) alkynyl, CR₈₁R₈₂OR₈₃, COR₈₄, COOR₈₅, orCONR₈₆R₈₇; wherein each of said alkyl and cycloalkyl being optionallysubstituted with one to three same or different cyano, phenyl, aryl,heteroaryl, heteroalicyclic, hydroxy, (C₁₋₆)alkoxy, halogen, benzyl,primary amine, secondary amine, tertiary amine, ammonium, nitro, thiol,thioether, alcohol, ether, acid, aldehyde, ketone, amide, amidine,guanidine, sulfone, sulfonamide, sulfamide, acyl sulfamide, sulfate,sulfuric acid, sulfamic acid, phosphate, phosphoric acid, boronic ester,boronic acid, squarate, squaric acid, oxime, hydrazine, peroxide, amongwhich ether, peroxide, thioether, secondary amine, tertiary amine,ammonium, ester, ketone, amide, amidine, oxime, hydrazine can be eitheracyclic or cyclic; heteroaryl is selected from the group consisting offuranyl, thienyl, thiazolyl, isothiazolyl, oxazolyl, isoxazolyl,imidazolyl, oxadiazolyl, thiadiazolyl, pyrazolyl, tetrazolyl, triazolyl,pyridinyl, pyrazinyl, pyridazinyl, and pyrimidinyl; J is selected fromthe group consisting of H, C₁-C₃₀ alkyl, C₃-C₁₅ cycloalkyl, C₄-C₃₀bicycloalkyl, C₅-C₃₀ tricycloalkyl, C₆-C₃₀ tetracycloalkyl, C₃-C₃₀alkenyl, C₄-C₃₀ cycloalkenyl, C₅-C₃₀ bicycloalkenyl, C₇-C₃₀tricycloalkenyl, C₉-C₃₀ tetracycloalkyl, C₁-C₃₀ amide, C₃-C₃₀ cyclicamide, C₁-C₃₀ amine, C₃-C₃₀ cyclic amine, C₂-C₃₀ ester, C₃-C₃₀ cyclicester, C₂-C₃₀ ether, C₃-C₃₀ cyclic ether, C₁-C₃₀ sulfonamide, C₃-C₃₀cyclic sulfonamide, C₂-C₃₀ sulfone, C₃-C₃₀ cyclic sulfone, C₂-C₃₀ urea,and C₃-C₃₀ cyclic urea; wherein said C₁-C₃₀ alkyl, C₃-C₃₀ cycloalkyl,C₄-C₃₀ bicycloalkyl, C₅-C₃₀ tricycloalkyl, C₆-C₃₀ tetracycloalkyl,C₃-C₃₀ alkenyl, C₄-C₃₀ cycloalkenyl, C₅-C₃₀ bicycloalkenyl, C₇-C₃₀tricycloalkenyl, C₉-C₃₀ tetracycloalkyl, C₁-C₃₀ amide, C₃-C₃₀ cyclicamide, C₁-C₃₀ amine, C₃-C₃₀ cyclic amine, C₂-C₃₀ ester, C₃-C₃₀ cyclicester, C₂-C₃₀ ether, C₃-C₃₀ cyclic ether, C₁-C₃₀ sulfonamide, C₃-C₃₀cyclic sulfonamide, C₂-C₃₀ sulfone, C₃-C₃₀ cyclic sulfone, C₂-C₃₀ urea,and C₃-C₃₀ cyclic urea is optionally substituted with one to three sameor different of the following functionalities: (C₁₋₆)alkyl,(C₃₋₆)cycloalkyl, cyano, phenyl, aryl, heteroaryl, heteroalicyclic,hydroxy, (C₁₋₆)alkoxy, halogen, benzyl, primary amine, secondary amine,tertiary amine, ammonium, nitro, thiol, thioether, alcohol, ether, acid,aldehyde, ketone, amide, amidine, guanidine, sulfone, sulfonamide,sulfamide, acyl sulfamide, sulfate, sulfuric acid, sulfamic acid,phosphate, phosphoric acid, boronic ester, boronic acid, squarate,squaric acid, oxime, hydrazine, peroxide, among which ether, peroxide,thioether, secondary amine, tertiary amine, ammonium, ester, ketone,amide, amidine, oxime, hydrazine can be either acyclic or cyclic; andR₈₁, R₈₂, R₈₃, R₈₄, R₈₅, R₈₆, and R₈₇ are each independently selectedfrom the group consisting of H, (C₁₋₆)alkyl, (C₃₋₆) cycloalkyl, (C₂₋₆)alkenyl, (C₄₋₆) cycloalkenyl, and (C₂₋₆) alkynyl.
 2. The compound asclaimed in claim 1, wherein one of a, b, c, d, and e is selected fromgroup B or group E.
 3. The compound as claimed in claim 1, wherein B isselected from the group consisting of C(O)NR⁴⁰R⁴¹, aryl, heteroaryl, andXR^(8a).
 4. The compound as claimed in claim 1, wherein Q is(C₁₋₆)alkyl.
 5. The compound as claimed in claim 1, wherein E is(C₂₋₆)alkenyl; optionally substituted with a member selected from thegroup consisting of phenyl, heteroaryl, —C(O)NR⁵⁶R⁵⁷, and C(O)R⁵⁷. 6.The compound as claimed in claim 1, wherein R⁷ is selected from thegroup of phenyl, pyridinyl, pyrazinyl, pyridazinyl, pyrimidinyl,thiazolyl, isothiazolyl, oxazolyl, isoxazolyl, imidazolyl, oxadiazolyl,thiadiazolyl, pyrazolyl, tetrazolyl, triazinyl and triazolyl; whereinsaid phenyl, pyridinyl, pyrazinyl, pyridazinyl, pyrimidinyl, thiazolyl,isothiazolyl, oxazolyl, isoxazolyl, imidazolyl, oxadiazolyl,thiadiazolyl, pyrazolyl, tetrazolyl, triazinyl and triazolyl areoptionally substituted with one to three same or different halogens orwith from one to three same or different substituents selected from thegroup F.
 7. The compound as claimed in claim 1, wherein F is selectedfrom the group consisting of (C₁₋₆)alkyl, (C₃₋₇)cycloalkyl, hydroxy,(C₁₋₆)alkoxy, cyano, halogen, —NR⁴²C(O)—(C₁₋₆)alkyl,—NR⁴²C(O)—(C₃₋₆)cycloalkyl, a 4, 5, or 6 membered ring cyclic N-lactam,—NR⁴²S(O)₂—(C₁₋₆)alkyl, —NR⁴²S(O)₂—(C₃₋₆)cycloalkyl, S(O)₂(C₁₋₆)alkyl,—S(O)2 NR⁴²R⁴³, NR⁴²R⁴³, (C₁₋₆)alkylC(O)NR⁴²R⁴³, C(O)NR⁴²R⁴³,NHC(O)NR⁴²R⁴³, OC(O)NR⁴²R⁴³, NHC(O)OR⁵⁴, (C₁₋₆)alkylNR⁴²R⁴³, COOR⁵⁴, and(C₁₋₆)alkylCOOR⁵⁴.
 8. The compound as claimed in claim 1, wherein X isNH, NCH₃, or O.
 9. The compound as claimed in claim 1, wherein R⁴⁰ andR⁴¹ are selected from the group of (a) hydrogen; (b) (C₁₋₆)alkyl or(C₃₋₇)cycloalkyl substituted with one to three same or differenthalogens or from one to two same or different substituents selected fromthe group F or different functional groups: (C₁₋₆)alkyl,(C₃₋₆)cycloalkyl, phenyl, aryl, heteroaryl, heteroalicyclic, hydroxy,(C₁₋₆)alkoxy, halogen, primary amine, secondary amine, tertiary amine,ammonium, alcohol, ether, acid, ketone, amide, amidine, guanidine,sulfone, sulfonamide, sulfamide, acyl sulfamide, sulfate, sulfuric acid,sulfamic acid, phosphate, phosphoric acid, boronic ester, boronic acid,squarate, squaric acid, oxime, hydrazine, among which ether, secondaryamine, tertiary amine, ammonium, ester, ketone, amide, amidine, oxime,hydrazine can be either acyclic or cyclic; heteroaryl is selected fromthe group consisting of thiazolyl, isothiazolyl, oxazolyl, isoxazolyl,imidazolyl, oxadiazolyl, thiadiazolyl, pyrazolyl, tetrazolyl, triazolyl,pyridinyl, pyrazinyl, pyridazinyl, and pyrimidinyl; and (c)(C₁₋₆)alkoxy, aryl, heteroaryl or heteroalicyclic; or R⁴⁰ and R⁴¹ takentogether with the nitrogen to which they are attached form a memberselected from the group consisting of azetidine, pyrrolidine,piperazine, 4—NMe piperazine, piperidine, azepine, and morpholine; andwherein said aryl, heteroaryl, and heteroalicyclic are optionallysubstituted with one to three same or different halogens or from one totwo same or different substituents selected from the group F; whereinfor R⁴⁰ and R⁴¹ aryl is phenyl; heteroaryl is a monocyclic system whichcontains from 3 to 6 ring atoms, including from 1 to 4 heteroatoms;heteroalicyclic is selected from the group consisting of azetidine,pyrrolidine, piperazine, piperidine, tetrahydrofuran, tetrahydropyran,azepine, and morpholine; provided when B is C(O)NR⁴⁰R⁴¹, at least one ofR⁴⁰ and R⁴¹ is not selected from groups (a) or (b).
 10. The compound asclaimed in claim 1, wherein R⁴² and R⁴³ are selected from the group ofhydrogen, (C₁₋₆)alkyl, a (C₁₋₆)alkoxy, (C₃₋₇)cycloalkyl, aryl,heteroaryl and heteroalicyclic; or R⁴² and R⁴³ taken together with thenitrogen to which they are attached form a member selected from thegroup consisting of azetidine, pyrrolidine, piperazine, 4—NMepiperazine, piperidine, azepine, and morpholine; and wherein said(C₁₋₆)alkyl, (C₁₋₆)alkoxy, (C₃₋₇)cycloalkyl, aryl, heteroaryl, andheteroalicyclic are optionally substituted with one to three same ordifferent halogens or from one to two same or different substituentsselected from the group G or different functional groups: (C₁₋₆)alkyl,(C₃₋₆)cycloalkyl, phenyl, aryl, heteroaryl, heteroalicyclic, hydroxy,(C₁₋₆)alkoxy, halogen, benzyl, primary amine, secondary amine, tertiaryamine, ammonium, alcohol, ether, acid, ketone, amide, amidine,guanidine, sulfone, sulfonamide, sulfamide, acyl sulfamide, sulfate,sulfuric acid, sulfamic acid, phosphate, phosphoric acid, boronic ester,boronic acid, squarate, squaric acid, oxime, hydrazine, among whichether, secondary amine, tertiary amine, ammonium, ester, ketone, amide,amidine, oxime, hydrazine can be either acyclic or cyclic; heteroaryl isselected from the group consisting of thiazolyl, isothiazolyl, oxazolyl,isoxazolyl, imidazolyl, oxadiazolyl, thiadiazolyl, pyrazolyl,tetrazolyl, triazolyl, pyridinyl, pyrazinyl, pyridazinyl, andpyrimidinyl; wherein for R⁴² and R⁴³ aryl is phenyl; heteroaryl is amonocyclic system which contains from 3 to 6 ring atoms, including from1 to 4 heteroatoms; heteroalicyclic is a member selected from the groupconsisting of azetidine, pyrrolidine, piperazine, piperidine,tetrahydrofuran, tetrahydropyran, azepine, and morpholine.
 11. Thecompound as claimed in claim 1, wherein G is selected from the groupconsisting of (C₁₋₆)alkyl, (C₃₋₇)cycloalkyl, hydroxy, (C₁₋₆)alkoxy,cyano, halogen, —NR⁴²C(O)—(C₁₋₆)alkyl, —NR⁴²C(O)—(C₃₋₆)cycloalkyl, a 4,5, or 6 membered ring cyclic N-lactam, —NR⁴²S(O)₂—(C₁₋₆)alkyl,—NR⁴²S(O)₂—(C₃₋₆)cycloalkyl, S(O)₂(C₁₋₆)alkyl, —S(O)2 NR⁴²R⁴³, NR⁴²R⁴³,(C₁₋₆)alkylC(O)NR⁴²R⁴³, C(O)NR⁴²R⁴³, NHC(O)NR⁴²R⁴³, OC(O)NR⁴²R⁴³,NHC(O)OR⁵⁴, (C₁₋₆)alkylNR⁴²R⁴³, COOR⁵⁴, and (C₁₋₆)alkylCOOR⁵⁴.
 12. Thecompound as claimed in claim 1, wherein A¹ and A² are selected from thegroup consisting of hydrogen, (C₁₋₆)alkyl, aryl, heteroaryl, COD⁴,COCOD⁴, COOD⁴, COND⁵D⁶, COCOND⁵D⁶, and COCOOD⁴.
 13. The compound asclaimed in claim 1, wherein D⁴, D⁵, and D⁶ are selected from the groupconsisting of H, C₁-C₁₀ alkyl, C₃-C₁₀ cycloalkyl, C₃-C₁₀ alkenyl, C₄-C₁₀cycloalkenyl, phenyl, heteroaryl, C₃-C₁₀ amide and C₃-C₁₀ ether;heteroaryl is selected from the group consisting of pyridinyl,pyrazinyl, pyridazinyl, pyrimidinyl, thiazolyl, isothiazolyl, oxazolyl,isoxazolyl, imidazolyl, oxadiazolyl, thiadiazolyl, pyrazolyl,tetrazolyl, triazinyl and triazolyl; provided the carbon atoms whichcomprise the carbon-carbon double bond of said C₃-C₁₀ alkenyl or thecarbon-carbon triple bond of said C₃-C₁₀ alkynyl are not the point ofattachment to the nitrogen to which D⁵ and D⁶ is attached; wherein saidC₁-C₁₀ alkyl, C₃-C₁₀ cycloalkyl, C₃-C₁₀ alkenyl, C₄-C₁₀ cycloalkenyl,aryl, phenyl, heteroaryl, C₃-C₁₀ amide and C₃-C₁₀ ether is optionallysubstituted with one to three same or different of the followingfunctionalities: (C₁₋₆)alkyl, (C₃₋₆)cycloalkyl, cyano, phenyl, aryl,heteroaryl, heteroalicyclic, hydroxy, (C₁₋₆)alkoxy, halogen, primaryamine, secondary amine, tertiary amine, ammonium, alcohol, ether, acid,ketone, amide, amidine, guanidine, sulfone, sulfonamide, sulfamide, acylsulfamide, sulfate, sulfuric acid, sulfamic acid, phosphate, phosphoricacid, boronic ester, boronic acid, squarate, squaric acid, oxime,hydrazine, peroxide, among which ether, thioether, secondary amine,tertiary amine, ammonium, ester, ketone, amide, amidine, oxime,hydrazine can be either acyclic or cyclic.
 14. The compound as claimedin claim 1, wherein I₁, I₂, I₃, I₄, I₅, I₆, I₇ and I₈ are selected fromthe group of H, (C₁₋₆)alkyl, (C₃₋₆) cycloalkyl, (C₂₋₆) alkenyl,CR₈₁R₈₂OR₈₃, COR₈₄, COOR₈₅, and CONR₈₆R₈₇.
 15. The compound as claimedin claim 1, wherein J is selected from the group consisting of H, C₁-C₁₀alkyl, C₃-C₁₀ cycloalkyl, C₄-C₁₅ bicycloalkyl, C₅-C₂₀ tricycloalkyl,C₆-C₂₅ tetracycloalkyl, C₃-C₁₀ alkenyl, C₄-C₁₀ cycloalkenyl, C₅-C₁₅bicycloalkenyl, C₇-C₂₀ tricycloalkenyl, C₉-C₂₅ tetracycloalkyl, C₁-C₁₀amide, C₃-C₁₀ cyclic amide, C₁-C₁₀ amine, C₃-C₁₀ cyclic amine, C₂-C₁₀ester, C₃-C₁₀ cyclic ester, C₂-C₁₀ ether, C₃-C₁₀ cyclic ether, C₁-C₁₀sulfonamide, C₃-C₁₀ cyclic sulfonamide, C₂-C₁₀ sulfone, C₃-C₁₀ cyclicsulfone, C₂-C₁₀ urea, and C₃-C₁₀ cyclic urea; wherein said H, C₁-C₁₀alkyl, C₃-C₁₀ cycloalkyl, C₄-C₁₅ bicycloalkyl, C₅-C₂₀ tricycloalkyl,C₆-C₂₅ tetracycloalkyl, C₃-C₁₀ alkenyl, C₄-C₁₀ cycloalkenyl, C₅-C₁₅bicycloalkenyl, C₇-C₂₀ tricycloalkenyl, C₉-C₂₅ tetracycloalkyl, C₁-C₁₀amide, C₃-C₁₀ cyclic amide, C₁-C₁₀ amine, C₃-C₁₀ cyclic amine, C₂-C₁₀ester, C₃-C₁₀ cyclic ester, C₂-C₁₀ ether, C₃-C₁₀ cyclic ether, C₁-C₁₀sulfonamide, C₃-C₁₀ cyclic sulfonamide, C₂-C₁₀ sulfone, C₃-C₁₀ cyclicsulfone, C₂-C₁₀ urea, and C₃-C₁₀ cyclic urea is optionally substitutedwith one to three same or different of the following functionalities:(C₁₋₆)alkyl, (C₃₋₆)cycloalkyl, cyano, phenyl, aryl, heteroaryl,heteroalicyclic, hydroxy, (C₁₋₆)alkoxy, halogen, primary amine,secondary amine, tertiary amine, ammonium, alcohol, ether, acid, ketone,amide, amidine, guanidine, sulfone, sulfonamide, sulfamide, acylsulfamide, sulfate, phosphate, squarate, oxime, among which ether,secondary amine, tertiary amine, ammonium, ester, ketone, amide,amidine, oxime, can be either acyclic or cyclic.
 16. The compound asclaimed in claim 1, wherein R₈₁, R₈₂, R₈₃, R₈₄, R₈₅, R₈₆, and R₈₇ areselected from the group consisting of H, (C₁₋₆)alkyl and (C₃₋₆)cycloalkyl.
 17. A compound which is selected from the group of:


18. A pharmaceutical composition which comprises an antiviral effectiveamount of one or more of the compounds of Formula I as claimed in claim1, together with one or more pharmaceutically acceptable carriers,excipients or diluents.
 19. A pharmaceutical composition which comprisesan antiviral effective amount of one or more of the compounds of FormulaI as claimed in claim 17, together with one or more pharmaceuticallyacceptable carriers, excipients or diluents.
 20. A method for treating amammal infected with HIV comprising administering to said mammal anantiviral effective amount of a compound of Formula I as claimed inclaim 1, and one or more pharmaceutically acceptable carriers,excipients or diluents.
 21. A method for treating a mammal infected withHIV comprising administering to said mammal an antiviral effectiveamount of a compound of Formula I as claimed in claim 17, and one ormore pharmaceutically acceptable carriers, excipients or diluents.